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Rau KK, Harrison BJ, Venkat G, Petruska SE, Taylor B, Hill CE, Petruska JC. Tissue damage-induced axon injury-associated responses in sensory neurons: requirements, prevention, and potential role in persistent post-surgical pain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.11.637320. [PMID: 39990499 PMCID: PMC11844497 DOI: 10.1101/2025.02.11.637320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Pain resulting from tissue damage, including surgical incision, is often only partially responsive to standard treatments focusing on inflammation, suggesting additional mechanisms are involved. Tissue damage leads to expression in dorsal root ganglion (DRG) sensory neurons of genes associated with axonal injury and regeneration, most notably activating transcription factor 3 (ATF3) and GAP-43. ATF3 expression is associated with sensitization of cellular physiology and enhanced amplitude/duration of a nociceptive reflex. It is unclear how tissue damage leads to these changes in the sensory neurons, but it could include direct damage to the tissue-innervating axons and inflammation-associated retrograde biochemical signalling. Using the CTM reflex to map innervation fields, we examined the necessity and sufficiency of incision, inflammation, and axonal conduction for induction of ATF3 in response to skin incision. Incision outside the innervation field, but close enough to induce inflammation inside the innervation field, was not sufficient to induce ATF3 expression in the field-innervating DRG. Incision inside the innervation field led to strong expression of ATF3. Anti-inflammatory treatments did not prevent this induction of ATF3. In rodent models of repeated injury - a major etiological factor for chronic pain - ATF3 expression was synergistically-increased and the threshold for paw-withdrawal to mechanical stimulation was significantly decreased for an extended duration. Together, these results suggest that actual damage to axons innervating the skin is both necessary and sufficient for induction of ATF3, expression of which appears additionally increased by repeated injury. Further, pre-treatment of the nerves innervating the incised skin with bupivacaine, a local anesthetic commonly used to reduce surgical pain, did not prevent induction of ATF3, indicating that conduction of action potentials is not necessary for induction of ATF3. We also determined that closure of incision with surgical glue significantly reduced incision-induced expression of GAP-43. Intriguingly, treatment with polyethylene glycol (PEG), known to enhance membrane integrity after injury among other effects, reduced incision-associated ATF3 expression and electrophysiological changes. These results suggest that pain resulting from tissue damage may arise from a mix of ATF3-/axonal-damage-associated mechanism as well as ATF3-independent inflammation-related mechanisms and therefore require a mix of approaches to achieve more complete control.
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Allgood JE, Whitney L, Goodwin J, Chong BSH, Brooks A, Pullan J. The Role of Pain Medications in Modulating Peripheral Nerve Injury Recovery. J Clin Pharmacol 2025; 65:411-423. [PMID: 39492597 DOI: 10.1002/jcph.6156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/15/2024] [Indexed: 11/05/2024]
Abstract
Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non-steroidal anti-inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma-aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI-related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti-inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage-gated Ca2+ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery.
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Affiliation(s)
- JuliAnne E Allgood
- Department of Neuroscience, University of Wyoming, Laramie, WY, USA
- Co-first authorship, Ivins, UT, USA
| | - Logan Whitney
- Department of Chemistry and Physics, Southern Utah University, Cedar City, UT, USA
- Co-first authorship, Ivins, UT, USA
| | - Jeffrey Goodwin
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT, USA
| | - Brian S H Chong
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT, USA
| | - Amanda Brooks
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT, USA
| | - Jessica Pullan
- Department of Chemistry and Physics, Southern Utah University, Cedar City, UT, USA
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Qi JY, Jin YC, Wang XS, Yang LK, Lu L, Yue J, Yang F, Liu YS, Jiang YL, Song DK, Lv T, Li XB, Zhang K, Liu SB. Ruscogenin Exerts Anxiolytic-Like Effect via Microglial NF-κB/MAPKs/NLRP3 Signaling Pathways in Mouse Model of Chronic Inflammatory Pain. Phytother Res 2024; 38:5417-5440. [PMID: 39267167 DOI: 10.1002/ptr.8325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/22/2024] [Accepted: 08/17/2024] [Indexed: 09/14/2024]
Abstract
Long-term inflammation can cause chronic pain and trigger patients' anxiety by sensitizing the central nervous system. However, effective drugs with few side effects for treating chronic pain-induced anxiety are still lacking. The anxiolytic and anti-inflammatory effects of ruscogenin (RUS), an important active compound in Ophiopogon japonicus, were evaluated in a mouse model of chronic inflammatory pain and N9 cells. RUS (5, 10, or 20 mg/kg/day, i.g.) was administered once daily for 7 days after CFA injection; pain- and anxiety-like behaviors were assessed in mice. Anti-inflammatory effect of RUS (0.1, 1, 10 μM) on N9 microglia after LPS treatment was evaluated. Inflammatory markers (TNF-α, IL-1β, IL-6, CD86, IL-4, ARG-1, and CD206) were measured using qPCR. The levels of IBA1, ROS, NF-κB, TLR4, P-IKK, P-IκBα, and P65, MAPKs (ERK, JNK, and P38), NLRP3 (caspase-1, ASC, and NLRP3) were detected by Western blotting or immunofluorescence staining. The potential target of RUS was validated by molecular docking and adeno-associated virus injection. Mice in CFA group exhibited allodynia and anxiety-like behaviors. LPS induced neuroinflammation in N9 cells. Both CFA and LPS increased the levels of IBA1, ROS, and inflammatory markers. RUS (10 mg/kg in vivo and 1 μM in vitro) alleviated these alterations through NF-κB/MAPKs/NLRP3 signaling pathways but had no effect on pain hypersensitivity. TLR4 strongly interacted with RUS, and TLR4 overexpression abolished the effects of RUS on anxiety and neuroinflammation. RUS exerts anti-inflammatory and anxiolytic effects via TLR4-mediated NF-κB/MAPKs/NLRP3 signaling pathways, which provides a basis for the treatment of chronic pain-induced anxiety.
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Affiliation(s)
- Jing-Yu Qi
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, China
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
- Department of Pharmacy, The Air Force Hospital of Eastern Theater Command, Nanjing, China
| | - Yu-Chen Jin
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, China
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Xin-Shang Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, China
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Liu-Kun Yang
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Liang Lu
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Jiao Yue
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Fan Yang
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yong-Sheng Liu
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Yong-Li Jiang
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Da-Ke Song
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, China
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Tao Lv
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Xu-Bo Li
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Kun Zhang
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Shui-Bing Liu
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, China
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China
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Huerta MÁ, Molina-Álvarez M, García MM, Tejada MA, Goicoechea C, Ghasemlou N, Ruiz-Cantero MC, Cobos EJ. The role of neutrophils in pain: systematic review and meta-analysis of animal studies. Pain 2024:00006396-990000000-00754. [PMID: 39450928 DOI: 10.1097/j.pain.0000000000003450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 09/10/2024] [Indexed: 10/26/2024]
Abstract
ABSTRACT The peripheral inflammatory response is an attractive therapeutic target for pain treatment. Neutrophils are the first circulating inflammatory cells recruited to sites of injury, but their contribution to pain outcomes is unclear. We performed a systematic review and meta-analysis of original preclinical studies, which evaluated the effect of preemptive neutrophil depletion on pain outcomes (PROSPERO registration number: CRD42022364004). Literature search (PubMed, January 19, 2023) identified 49 articles, which were meta-analyzed using a random-effects model. The risk of bias was evaluated using SYRCLE's tool. The pooled effect considering all studies showed that neutrophil depletion induced a consistent pain reduction. Inflammatory, joint, neuropathic, and visceral pain showed significant pain alleviation by neutrophil depletion with medium-large effect sizes. However, muscle and postoperative pain were not significantly alleviated by neutrophil depletion. Further analysis showed a differential contribution of neutrophils to pain outcomes. Neutrophils had a higher impact on mechanical hyperalgesia, followed by nociceptive behaviors and mechanical allodynia, with a smaller contribution to thermal hyperalgesia. Interspecies (mice or rats) differences were not appreciated. Analyses regarding intervention unveiled a lower pain reduction for some commonly used methods for neutrophil depletion, such as injection of antineutrophil serum or an anti-Gr-1 antibody, than for other agents such as administration of an anti-Ly6G antibody, fucoidan, vinblastine, CXCR1/2 inhibitors, and etanercept. In conclusion, the contribution of neutrophils to pain depends on pain etiology (experimental model), pain outcome, and the neutrophil depletion strategy. Further research is needed to improve our understanding on the mechanisms of these differences.
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Affiliation(s)
- Miguel Á Huerta
- Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Biosanitary Research Institute ibs.GRANADA, Granada, Spain
| | - Miguel Molina-Álvarez
- Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Rey Juan Carlos University, Asociated Unit I+D+i Instituto de Química Médica (IQM) CSIC-URJC, Alcorcón, Spain
- High Performance Experimental Pharmacology Research Group, Rey Juan Carlos University (PHARMAKOM), Alcorcón, Spain
| | - Miguel M García
- Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Rey Juan Carlos University, Asociated Unit I+D+i Instituto de Química Médica (IQM) CSIC-URJC, Alcorcón, Spain
- High Performance Experimental Pharmacology Research Group, Rey Juan Carlos University (PHARMAKOM), Alcorcón, Spain
| | - Miguel A Tejada
- Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Biosanitary Research Institute ibs.GRANADA, Granada, Spain
| | - Carlos Goicoechea
- Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Rey Juan Carlos University, Asociated Unit I+D+i Instituto de Química Médica (IQM) CSIC-URJC, Alcorcón, Spain
- High Performance Experimental Pharmacology Research Group, Rey Juan Carlos University (PHARMAKOM), Alcorcón, Spain
| | - Nader Ghasemlou
- Pain Chronobiology & Neuroimmunology Laboratory, Departments of Anesthesiology and Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - M Carmen Ruiz-Cantero
- Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, Spain
| | - Enrique J Cobos
- Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Biosanitary Research Institute ibs.GRANADA, Granada, Spain
- Teófilo Hernando Institute for Drug Discovery, Madrid, Spain
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Wilson HJE, Patton D, Budri AMV, Boland F, O'Connor T, McDonnell CO, Rai H, Moore ZEH. The correlation between sub-epidermal moisture assessment and other early indicators of pressure ulcer development: A prospective cohort observational study. Part 2. The correlation between sub-epidermal moisture assessment, temperature, epidermal hydration and pain. Int Wound J 2024; 21:e70058. [PMID: 39379178 PMCID: PMC11461043 DOI: 10.1111/iwj.70058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/30/2024] [Accepted: 09/03/2024] [Indexed: 10/10/2024] Open
Abstract
There is growing interest in the roles of temperature, epidermal hydration (EH) and pain in pressure ulcer (PU) development. Investigating correlations between these measures and sub-epidermal moisture (SEM) will address this knowledge deficit. A prospective observational study enrolled 60 surgical patients from February to November 2021. SEM, temperature, EH and pain were assessed using a SEM scanner, thermography imaging, skin hydration device and numeric pain intensity scale, respectively. Measurements were taken at the sacrum, both heels and a control site, before and after surgery for 3 days. Data were analysed using Pearson or Spearman's correlation. Of the participants, 50% were male with a mean age of 58 years (±13.46). Low positive/negative correlations between SEM and temperature were found at the sacrum. However, after removing outliers, these results were not statistically significant. Other sites and follow-up days showed negligible correlations. No evidence of a correlation, to low correlations between SEM and EH were observed, but unreliable due to little variation in EH at the heels. Pain showed negligible correlations with SEM. This study did not find consistent evidence of a correlation between SEM, temperature, EH and pain, highlighting the unreliability of temperature and EH for early PU detection. Post-operative pain may also confound accurate pain assessments.
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Affiliation(s)
- Hannah Jane Elizabeth Wilson
- Skin Wounds and Trauma Research CentreRCSI University of Medicine and Health SciencesDublinIreland
- School of Nursing and MidwiferyRCSI University of Medicine and Health SciencesDublinIreland
| | - Declan Patton
- Skin Wounds and Trauma Research CentreRCSI University of Medicine and Health SciencesDublinIreland
- School of Nursing and MidwiferyRCSI University of Medicine and Health SciencesDublinIreland
- Fakeeh College of Health SciencesJeddahSaudi Arabia
- School of Nursing and MidwiferyGriffith UniversityNathanAustralia
- Honorary Senior Fellow, Faculty of Science, Medicine and HealthUniversity of WollongongWollongongAustralia
| | - Aglecia Moda Vitoriano Budri
- Skin Wounds and Trauma Research CentreRCSI University of Medicine and Health SciencesDublinIreland
- School of Nursing and MidwiferyRCSI University of Medicine and Health SciencesDublinIreland
| | - Fiona Boland
- Data Science Centre, School of Population HealthRCSI University of Medicine and Health SciencesDublinIreland
| | - Tom O'Connor
- Skin Wounds and Trauma Research CentreRCSI University of Medicine and Health SciencesDublinIreland
- School of Nursing and MidwiferyRCSI University of Medicine and Health SciencesDublinIreland
- Fakeeh College of Health SciencesJeddahSaudi Arabia
- School of Nursing and MidwiferyGriffith UniversityNathanAustralia
- Lida InstituteShanghaiChina
| | | | - Himanshu Rai
- Cardiovascular Research Institute Dublin (CVRI Dublin)Mater Private Network IrelandDublinIreland
- School of Pharmacy and Biomolecular sciencesRCSI, University of Medicine and Health SciencesDublinIreland
| | - Zena Elizabeth Helen Moore
- Skin Wounds and Trauma Research CentreRCSI University of Medicine and Health SciencesDublinIreland
- School of Nursing and MidwiferyRCSI University of Medicine and Health SciencesDublinIreland
- Fakeeh College of Health SciencesJeddahSaudi Arabia
- School of Nursing and MidwiferyGriffith UniversityNathanAustralia
- Lida InstituteShanghaiChina
- Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonAustralia
- Department of Public Health, Faculty of Medicine and Health SciencesGhent UniversityGhentBelgium
- University of WalesCardiffUK
- National Health and Medical Research Council Centre of Research Excellence in Wiser Wound CareMenzies Health Institute QueenslandGold CoastAustralia
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Jensen KL, Christensen NR, Goddard CM, Jager SE, Noes-Holt G, Kanneworff IB, Jakobsen A, Jiménez-Fernández L, Peck EG, Sivertsen L, Comaposada Baro R, Houser GA, Mayer FP, Diaz-delCastillo M, Topp ML, Hopkins C, Thomsen CD, Soltan ABI, Tidemand FG, Arleth L, Heegaard AM, Sørensen AT, Madsen KL. Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models. JCI Insight 2024; 9:e170976. [PMID: 39287978 PMCID: PMC11530130 DOI: 10.1172/jci.insight.170976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 09/10/2024] [Indexed: 09/19/2024] Open
Abstract
Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting side effects, including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid-conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated PICK1 inhibitor, myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favorable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity as well as ongoing hypersensitivity and anxiodepressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks after spared nerve injury surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection.
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Affiliation(s)
| | - Nikolaj Riis Christensen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, and
| | | | - Sara Elgaard Jager
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
| | - Gith Noes-Holt
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
| | - Ida Buur Kanneworff
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alexander Jakobsen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
| | | | - Emily G. Peck
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Line Sivertsen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
| | | | - Grace Anne Houser
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
| | - Felix Paul Mayer
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
| | - Marta Diaz-delCastillo
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marie Løth Topp
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience
| | - Chelsea Hopkins
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cecilie Dubgaard Thomsen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ahmed Barakat Ibrahim Soltan
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Frederik Grønbæk Tidemand
- X-ray and Neutron Science, Niels Bohr Institute, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Lise Arleth
- X-ray and Neutron Science, Niels Bohr Institute, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Anne-Marie Heegaard
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Zoltick AH, Mann S, Coetzee JF. Pain pathophysiology and pharmacology of cattle: how improved understanding can enhance pain prevention, mitigation, and welfare. FRONTIERS IN PAIN RESEARCH 2024; 5:1396992. [PMID: 39258013 PMCID: PMC11385012 DOI: 10.3389/fpain.2024.1396992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 07/29/2024] [Indexed: 09/12/2024] Open
Abstract
Globally, humans rely on cattle for food production; however, there is rising societal concern surrounding the welfare of farm animals. From a young age, cattle raised for dairy and beef production experience pain caused by routine management procedures and common disease conditions. The fundamental mechanisms, nociceptive pathways, and central nervous system structures required for pain perception are highly conserved among mammalian species. However, there are limitations to a comparative approach to pain assessment due to interspecies differences in the expression of pain. The stoicism of prey species may impede pain identification and lead to the assumption that cattle lack pain sensitivity. This highlights the importance of establishing validated bovine-specific indicators of pain-a prerequisite for evidence-based pain assessment and mitigation. Our first objective is to provide an overview of pain pathophysiology to illustrate the importance of targeted analgesia in livestock medicine and the negative welfare outcomes associated with unmitigated pain. This is followed by a review of available analgesics, the regulations governing their use, and barriers to implementation of on-farm pain management. We then investigate the current research undertaken to evaluate the pain response in cattle-a critical aspect of the drug approval process. With an emphasis on emerging research in animal cognition and pain pathology, we conclude by discussing the significant influence that pain has on cattle welfare and areas where further research and modified practices are indicated.
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Affiliation(s)
- Abigale H Zoltick
- Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA, United States
- Department of Population Medicine and Diagnostic Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, United States
| | - Sabine Mann
- Department of Population Medicine and Diagnostic Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, United States
| | - Johann F Coetzee
- Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, United States
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Raff H, Hainsworth KR, Woyach VL, Weihrauch D, Wang X, Dean C. Probiotic and high-fat diet: effects on pain assessment, body composition, and cytokines in male and female adolescent and adult rats. Am J Physiol Regul Integr Comp Physiol 2024; 327:R123-R132. [PMID: 38780441 PMCID: PMC11444502 DOI: 10.1152/ajpregu.00082.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/02/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024]
Abstract
Obesity in adolescence is increasing in frequency and is associated with elevated proinflammatory cytokines and chronic pain in a sex-dependent manner. Dietary probiotics may mitigate these detrimental effects of obesity. Using a Long-Evans adolescent and adult rat model of overweight (high-fat diet (HFD) - 45% kcal from fat from weaning), we determined the effect of a single-strain dietary probiotic [Lactiplantibacillus plantarum 299v (Lp299v) from weaning] on the theoretically increased neuropathic injury-induced pain phenotype and inflammatory cytokines. We found that although HFD increased fat mass, it did not markedly affect pain phenotype, particularly in adolescence, but there were subtle differences in pain in adult male versus female rats. The combination of HFD and Lp299v augmented the increase in leptin in adolescent females. There were many noninteracting main effects of age, diet, and probiotic on an array of cytokines and adipokines with adults being higher than adolescents, HFD higher than the control diet, and a decrease with probiotic compared with placebo. Of particular interest were the probiotic-induced increases in IL12p70 in female adolescents on an HFD. We conclude that a more striking pain phenotype could require a higher and longer duration caloric diet or a different etiology of pain. A major strength of our study was that a single-strain probiotic had a wide range of inhibiting effects on most proinflammatory cytokines. The positive effect of the probiotic on leptin in female adolescent rats is intriguing and worthy of exploration.NEW & NOTEWORTHY A single-strain probiotic (Lp299v) had a wide range of inhibiting effects on most proinflammatory cytokines (especially IL12p70) measured in this high-fat diet rat model of mild obesity. The positive effect of probiotic on leptin in female adolescent rats is intriguing and worthy of exploration.
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Affiliation(s)
- Hershel Raff
- Division of Endocrinology and Molecular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Keri R Hainsworth
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Jane B. Pettit Pain and Headache Center, Children's Wisconsin, Milwaukee, Wisconsin, United States
| | - Victoria L Woyach
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Research Division, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States
| | - Dorothee Weihrauch
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Research Division, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States
| | - Xuemeng Wang
- Center for Advancing Population Science, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Caron Dean
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Research Division, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States
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Nikitas J, Yanagawa J, Sacks S, Hui EK, Lee A, Deng J, Abtin F, Suh R, Lee JM, Toste P, Burt BM, Revels SL, Cameron RB, Moghanaki D. Pathophysiology and Management of Chest Wall Pain after Surgical and Non-Surgical Local Therapies for Lung Cancer. JTO Clin Res Rep 2024; 5:100690. [PMID: 39077624 PMCID: PMC11284817 DOI: 10.1016/j.jtocrr.2024.100690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/18/2024] [Accepted: 05/08/2024] [Indexed: 07/31/2024] Open
Abstract
Chest wall pain syndromes can emerge following local therapies for lung cancer and can adversely affect patients' quality-of-life. This can occur after lung surgery, radiation therapy, or percutaneous image-guided thermal ablation. This review describes the multifactorial pathophysiology of chest wall pain syndromes that develop following surgical and non-surgical local therapies for lung cancer and summarizes evidence-based management strategies for inflammatory, neuropathic, myofascial, and osseous pain. It discusses a step-wise approach to treating chest wall pain that begins with non-opioid oral analgesics and includes additional pharmacologic treatments as clinically indicated, such as anticonvulsants, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and various topical treatments. For myofascial pain, physical medicine techniques, such as acupuncture, trigger point injections, deep tissue massage, and intercostal myofascial release can also offer pain relief. For severe or refractory cases, opioid analgesics, intercostal nerve blocks, or intercostal nerve ablations may be indicated. Fortunately, palliation of treatment-related chest wall pain syndromes can be managed by most clinical providers, regardless of the type of local therapy utilized for a patient's lung cancer treatment. In cases where a patient's pain fails to respond to initial medical management, clinicians can consider referring to a pain specialist who can tailor a more specific pharmacologic approach or perform a procedural intervention to relieve pain.
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Affiliation(s)
- John Nikitas
- Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California
| | - Jane Yanagawa
- Division of Thoracic Surgery, University of California, Los Angeles, Los Angeles, California
| | - Sandra Sacks
- Department of Anesthesiology, University of California, Los Angeles, Los Angeles, California
| | - Edward K. Hui
- Center for East-West Medicine, University of California, Los Angeles, Los Angeles, California
| | - Alan Lee
- Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California
| | - Jie Deng
- Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California
| | - Fereidoun Abtin
- Thoracic Imaging and Intervention, Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, California
| | - Robert Suh
- Thoracic Imaging and Intervention, Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, California
| | - Jay M. Lee
- Division of Thoracic Surgery, University of California, Los Angeles, Los Angeles, California
| | - Paul Toste
- Division of Thoracic Surgery, University of California, Los Angeles, Los Angeles, California
| | - Bryan M. Burt
- Division of Thoracic Surgery, University of California, Los Angeles, Los Angeles, California
| | - Sha’Shonda L. Revels
- Division of Thoracic Surgery, University of California, Los Angeles, Los Angeles, California
| | - Robert B. Cameron
- Division of Thoracic Surgery, University of California, Los Angeles, Los Angeles, California
| | - Drew Moghanaki
- Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California
- Radiation Oncology Service, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California
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10
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Alalami K, Goff J, Grimson H, Martin O, McDonald E, Mirza T, Mistry D, Ofodile A, Raja S, Shaker T, Sleibi D, Forget P. Does Topical Capsaicin Affect the Central Nervous System in Neuropathic Pain? A Narrative Review. Pharmaceuticals (Basel) 2024; 17:842. [PMID: 39065693 PMCID: PMC11279538 DOI: 10.3390/ph17070842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/21/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Research has been conducted investigating the neuronal pathways responsible for the generation of chronic neuropathic pain, including the components of it in conditions such as chronic post-surgical pain, phantom limb pain, and cluster headaches. Forming part of the management of such conditions, capsaicin as a molecule has proven effective. This review has investigated the central nervous system modifications exhibited in such conditions and the pharmacological mechanisms of capsaicin relevant to this. The current paradigm for explaining topical capsaicin-induced analgesia is that TRPV1-mediated calcium ion influx induces calpain, in turn causing axonal ablation and functional defunctionalisation in the PNS (Peripheral Nervous System). Demonstrated through the analysis of existing data, this review demonstrates the changes seen in the CNS (Central Nervous System) in chronic neuropathic pain, as well as some of the evidence for capsaicin modulation on the CNS. Further supporting this, the specific molecular mechanisms of capsaicin-induced analgesia will also be explored, including the action of TRPV1, as well as discussing the further need for clinical research into this area of uncertainty due to the limited specific data with suitable parameters. Further research this review identified as potentially useful in this field included fMRI (functional Magnetic Resonance Imaging) studies, though more specific observational studies of patients who have already been administered capsaicin as a current treatment may prove helpful in studying the modification of the CNS in the long term.
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Affiliation(s)
- Kareem Alalami
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Jenna Goff
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Hannah Grimson
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Oliver Martin
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Eloise McDonald
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Thonima Mirza
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Dhruvi Mistry
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Adanma Ofodile
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Sara Raja
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Tooba Shaker
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Danah Sleibi
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB24 3FX, UK; (K.A.); (D.S.)
| | - Patrice Forget
- Epidemiology Group, Institute of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Polwarth Building, Foresterhill Health Campus, Aberdeen AB25 2ZN, UK
- Department of Anaesthesia, NHS Grampian, Aberdeen AB25 2ZN, UK
- Pain and Opioids after Surgery (PANDOS) Research Groups, European Society of Anaesthesiology and Intensive Care, 1000 Brussels, Belgium
- Anesthesia Critical Care, Emergency and Pain Medicine Division, 30900 Nîmes University Hospital, IMAGINE UR UM 103, Montpellier University, 30900 Nîmes, France
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11
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Nikoohemmat M, Farmani D, Moteshakereh SM, Salehi S, Rezaee L, Haghparast A. Intra-accumbal orexinergic system contributes to the stress-induced antinociceptive behaviors in the animal model of acute pain in rats. Behav Pharmacol 2024; 35:92-102. [PMID: 38055726 DOI: 10.1097/fbp.0000000000000763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023]
Abstract
Stress and pain are interleaved at numerous levels - influencing each other. Stress can increase the nociception threshold in animals, long-known as stress-induced analgesia (SIA). Orexin is known as a neuropeptide that modulates pain. The effect of stress on the mesolimbic system in the modulation of pain is known. The role of the intra-accumbal orexin receptors in the modulation of acute pain by forced swim stress (FSS) is unclear. In this study, 117 adult male albino Wistar rats (270-300 g) were used. The animals were unilaterally implanted with cannulae above the NAc. The antagonist of the orexin-1 receptor (OX1r), SB334867, and antagonist of the orexin-2 receptor (OX2r), TCS OX2 29, were microinjected into the NAc in different doses (1, 3, 10, and 30 nmol/0.5 µl DMSO) before exposure to FSS for a 6-min period. The tail-flick test was carried out as an assay nociception of acute pain, and the nociceptive threshold [tail-flick latency (TFL)] was measured for 60-minute. The findings demonstrated that exposure to acute stress could remarkably increase the TFLs and antinociceptive responses. Moreover, intra-accumbal microinjection of SB334867 or TCS OX2 29 blocked the antinociceptive effect of stress in the tail-flick test. The contribution of orexin receptors was almost equally modulating SIA. The present study's findings suggest that OX1r and OX2r within the NAc modulate stress-induced antinociceptive responses. The intra-accumbal microinjection of orexin receptors antagonists declares inducing antinociceptive responses by FSS in acute pain. Proposedly, intra-accumbla orexinergic receptors have a role in the development of SIA.
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Affiliation(s)
- Mohammad Nikoohemmat
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences
| | - Danial Farmani
- Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences
| | | | - Sakineh Salehi
- Department of Medicine, Ardabil Medical Sciences Branch, Islamic Azad University, Ardabil, Iran
| | - Laleh Rezaee
- Institute of Pathophysiology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences
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12
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Garcia MM, Corrales P, Huerta MÁ, Czachorowski MJ, López-Miranda V, Medina-Gómez G, Cobos EJ, Goicoechea C, Molina-Álvarez M. Adults with excess weight or obesity, but not with overweight, report greater pain intensities than individuals with normal weight: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2024; 15:1340465. [PMID: 38510698 PMCID: PMC10950917 DOI: 10.3389/fendo.2024.1340465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 02/19/2024] [Indexed: 03/22/2024] Open
Abstract
Context Over 1.9 billion adult people have overweight or obesity. Considered as a chronic disease itself, obesity is associated with several comorbidities. Chronic pain affects approximately 60 million people and its connection with obesity has been displayed in several studies. However, controversial results showing both lower and higher pain thresholds in subjects with obesity compared to individuals with normal weight and the different parameters used to define such association (e.g., pain severity, frequency or duration) make it hard to draw straight forward conclusions in the matter. The objective of this article is to examine the relationship between overweight and obesity (classified with BMI as recommended by WHO) and self-perceived pain intensity in adults. Methods A literature search was conducted following PRISMA guidelines using the databases CINAHL, Cochrane Library, EMBASE, PEDro, PubMed, Scopus and Web of Science to identify original studies that provide BMI values and their associated pain intensity assessed by self-report scales. Self-report pain scores were normalized and pooled within meta-analyses. The Cochrane's Q test and I2 index were used to clarify the amount of heterogeneity; meta-regression was performed to explore the relationship between each outcome and the risk of bias. Results Of 2194 studies, 31 eligible studies were identified and appraised, 22 of which provided data for a quantitative analysis. The results herein suggested that adults with excess weight (BMI ≥ 25.0) or obesity (BMI ≥ 30.0) but not with overweight (pre-obesity) alone (BMI 25.0-29.9), are more likely to report greater intensities of pain than individuals of normal weight (BMI 18.5-24.9). Subgroup analyses regarding the pathology of the patients showed no statistically significant differences between groups. Also, influence of age in the effect size, evaluated by meta-regression, was only observed in one of the four analyses. Furthermore, the robustness of the findings was supported by two different sensitivity analyses. Conclusion Subjects with obesity and excess weight, but not overweight, reported greater pain intensities than individuals with normal weight. This finding encourages treatment of obesity as a component of pain management. More research is required to better understand the mechanisms of these differences and the clinical utility of the findings. Systematic Review Registration https://doi.org/10.17605/OSF.IO/RF2G3, identifier OSF.IO/RF2G3.
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Affiliation(s)
- Miguel M Garcia
- Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Unidad Asociada de I+D+i al Instituto de Química Médica (IQM) CSIC-URJC, Alcorcón, Spain
- High Performance Experimental Pharmacology Research Group, Universidad Rey Juan Carlos (PHARMAKOM), Alcorcón, Spain
- Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Alcorcón, Spain
| | - Patricia Corrales
- Area of Biochemistry, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Alcorcón, Spain
- High Performance Research Group in the Study of the Molecular Mechanisms of Glucolipotoxicity and Insulin Resistance: Implications in Obesity, Diabetes and Metabolic Syndrome, Universidad Rey Juan Carlos (LIPOBETA), Alcorcón, Spain
- Consolidated Research Group on Obesity and Type 2 Diabetes: Adipose Tissue Biology (BIOFAT), Universidad Rey Juan Carlos, Alcorcón, Spain
| | - Miguel Á Huerta
- Department of Pharmacology and Neurosciences Institute (Biomedical Research Center), Universidad de Granada, Granada, Spain
- Biosanitary Research Institute ibs.GRANADA, Granada, Spain
| | | | - Visitación López-Miranda
- Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Unidad Asociada de I+D+i al Instituto de Química Médica (IQM) CSIC-URJC, Alcorcón, Spain
- High Performance Experimental Pharmacology Research Group, Universidad Rey Juan Carlos (PHARMAKOM), Alcorcón, Spain
- Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Alcorcón, Spain
| | - Gema Medina-Gómez
- Area of Biochemistry, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Alcorcón, Spain
- High Performance Research Group in the Study of the Molecular Mechanisms of Glucolipotoxicity and Insulin Resistance: Implications in Obesity, Diabetes and Metabolic Syndrome, Universidad Rey Juan Carlos (LIPOBETA), Alcorcón, Spain
| | - Enrique J Cobos
- Department of Pharmacology and Neurosciences Institute (Biomedical Research Center), Universidad de Granada, Granada, Spain
- Biosanitary Research Institute ibs.GRANADA, Granada, Spain
- Teófilo Hernando Institute for Drug Discovery, Madrid, Spain
| | - Carlos Goicoechea
- Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Unidad Asociada de I+D+i al Instituto de Química Médica (IQM) CSIC-URJC, Alcorcón, Spain
- High Performance Experimental Pharmacology Research Group, Universidad Rey Juan Carlos (PHARMAKOM), Alcorcón, Spain
- Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Alcorcón, Spain
| | - Miguel Molina-Álvarez
- Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Unidad Asociada de I+D+i al Instituto de Química Médica (IQM) CSIC-URJC, Alcorcón, Spain
- High Performance Experimental Pharmacology Research Group, Universidad Rey Juan Carlos (PHARMAKOM), Alcorcón, Spain
- Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Alcorcón, Spain
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13
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Dainese P, DE Mits S, Wittoek R, VAN Ginckel A, Huysse W, Mahieu H, Stautemas J, Calders P. Neuropathic-like pain in knee osteoarthritis: exploring differences in knee loading and inflammation. A cross-sectional study. Eur J Phys Rehabil Med 2024; 60:62-73. [PMID: 37934188 PMCID: PMC10938037 DOI: 10.23736/s1973-9087.23.07877-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 09/04/2023] [Accepted: 10/13/2023] [Indexed: 11/08/2023]
Abstract
BACKGROUND A subgroup of patients with knee osteoarthritis (OA) reports symptoms attributable to a neuropathic cause. Little to no attention has been invested on investigating differences in knee loading and inflammation in these patients. AIM To explore differences in inflammation and knee loading in patients with knee OA categorized based on the presence of neuropathic-like pain. DESIGN Cross-sectional study. SETTING Ghent University Hospital, Ghent, Belgium. POPULATION Knee OA patients. METHODS cross-sectional analysis of data from 96 patients (mean age 64.18±7.11 years) with primary knee OA participating in a randomized controlled trial. Participants were divided into three groups (unlikely, possible and indication of neuropathic-like pain) according to the modified painDETECT questionnaire (mPDQ). Data on demographics, symptoms and physical function were obtained by questionnaires. Effusion/synovitis and bone marrow lesions (BMLs) were measured using magnetic resonance imaging. Knee loading variables (knee adduction moment [KAM], KAM impulse, and knee flexion moment [KFM]) were assessed by 3D-motion analysis. One-way analysis of covariance (ANCOVA), Chi-square test and curve analyses were used to analyze continuous, categorical and loading variables respectively. Multinomial logistic regression was used to identify predictors for neuropathic-like pain. RESULTS Patients with indication of neuropathic-like pain exhibited higher KAM impulse compared to those with no indication of neuropathic-like pain (standard mean difference (SMD): -0.036 Nm normalized to body weight and height per second, 95% CI: -0.071, -0.001) along with greater pain intensity (SMD: 3.87 units, 95% CI: 1.90, 5.84), stiffness (SMD: 1.34 units, 95% CI: 0.19, 2.48) and worse physical function (SMD: 13.98 units 95% CI: 7.52, 20.44). Curve analysis showed no significant differences in KFM and KAM between groups. Effusion/synovitis and BMLs did not differ significantly between groups. The best predictors for indication of neuropathic-like pain were KAM impulse, Hoffa and sex. CONCLUSIONS Knee OA patients with indication of neuropathic-like pain exhibited higher dynamic medial loading, greater pain severity and worse physical function, while inflammatory markers were not significantly different across mPDQ groups. Future longitudinal studies are warranted to strengthen the evidence and establish mechanisms to explain associations between neuropathic-like pain and knee loading. CLINICAL REHABILITATION IMPACT Knee loading is a modifiable factor and patients with neuropathic-like pain may benefit from offloading interventions.
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Affiliation(s)
- Paolo Dainese
- Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Ghent, Belgium
| | - Sophie DE Mits
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- Smart Space, Ghent University Hospital, Ghent, Belgium
| | - Ruth Wittoek
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Ans VAN Ginckel
- Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Ghent, Belgium
| | - Wouter Huysse
- Department of Radiology, Ghent University Hospital, Ghent, Belgium
| | - Hanne Mahieu
- Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Ghent, Belgium
| | - Jan Stautemas
- Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Ghent, Belgium
| | - Patrick Calders
- Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Ghent, Belgium -
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14
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da Silva MDV, Piva M, Martelossi-Cebinelli G, Stinglin Rosa Ribas M, Hoffmann Salles Bianchini B, K Heintz O, Casagrande R, Verri WA. Stem cells and pain. World J Stem Cells 2023; 15:1035-1062. [PMID: 38179216 PMCID: PMC10762525 DOI: 10.4252/wjsc.v15.i12.1035] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 11/06/2023] [Accepted: 11/30/2023] [Indexed: 12/26/2023] Open
Abstract
Pain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience. For years, science has sought to find treatment alternatives, with minimal side effects, to relieve pain. However, the currently available pharmacological options on the market show significant adverse events. Therefore, the search for a safer and highly efficient analgesic treatment has become a priority. Stem cells (SCs) are non-specialized cells with a high capacity for replication, self-renewal, and a wide range of differentiation possibilities. In this review, we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain. With the advantage of multiple administration routes and dosages, therapies based on SCs for pain relief have demonstrated meaningful results with few downsides. Nonetheless, there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs. Thus, this is an evolving field that merits further investigation towards the development of SC-based analgesic therapies, and this review will approach all of these aspects.
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Affiliation(s)
- Matheus Deroco Veloso da Silva
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Maiara Piva
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Geovana Martelossi-Cebinelli
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Mariana Stinglin Rosa Ribas
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Beatriz Hoffmann Salles Bianchini
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Olivia K Heintz
- Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01655, United States
| | - Rubia Casagrande
- Department of Pharmaceutical Sciences, Center of Health Science, State University of Londrina, Londrina 86038-440, Paraná, Brazil
| | - Waldiceu A Verri
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, Center of Biological Sciences, State University of Londrina, Londrina 86057-970, Paraná, Brazil.
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15
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Müller M, Schmucker C, Naumann J, Schlueter N, Huber R, Lederer AK. Acupuncture in management of acute dental pain - A systematic review and meta-analysis. JAPANESE DENTAL SCIENCE REVIEW 2023; 59:114-128. [PMID: 36950225 PMCID: PMC10025006 DOI: 10.1016/j.jdsr.2023.02.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 02/16/2023] [Accepted: 02/23/2023] [Indexed: 03/12/2023] Open
Abstract
Acute dental pain is a common issue leading to dental consultation. Besides causal therapy, patients are treated with acupuncture, but efficacy in acute dental pain is still not clarified. We aimed to evaluate results of recent research to estimate the efficacy of acupuncture compared to pain-relieving approaches in treatment of acute dental pain. A systematic review of controlled trials being published between database inception and 2020 were conducted to evaluate the efficacy of acupuncture (alone or as complementary therapy) compared to local anesthesia or conventional analgesic medications in acute dental pain (intraoperatively and postoperatively) and to clarify whether acupuncture reduces the use of postoperative analgesic medications. Of 1672 publications, 23 publications met the inclusion criteria. From these, 11 randomized controlled trials (n = 668) reported on the efficacy of acupuncture on postoperative acute dental pain. Patients, who received acupuncture, showed lower pain scores postoperatively compared to sham acupuncture (Relative Risk -0.77, 95% Confidence interval -1.52 to -0.03). Overall, the results suggest a potential role of acupuncture in improving acute dental pain intraoperatively and postoperatively as well as improving the efficacy of local anesthesia, but the results are limited due to methodological shortcomings emphasizing the necessity for future high-quality research.
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Affiliation(s)
- Moritz Müller
- Center for Complementary Medicine, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Christine Schmucker
- Institute for Evidence in Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Johannes Naumann
- European Institute for Physical Therapy and Balneology (EIPB), 79106 Freiburg, Germany
| | - Nadine Schlueter
- Hannover Medical School (MHH), Department of Conservative Dentistry, Periodontology and Preventive Dentistry, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
| | - Roman Huber
- Center for Complementary Medicine, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Ann-Kathrin Lederer
- Center for Complementary Medicine, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of General, Visceral and Transplant Surgery, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
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16
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Adhya P, Vaidya B, Sharma SS. BTD: A TRPC5 activator ameliorates mechanical allodynia in diabetic peripheral neuropathic rats by modulating TRPC5-CAMKII-ERK pathway. Neurochem Int 2023; 170:105609. [PMID: 37673218 DOI: 10.1016/j.neuint.2023.105609] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 09/02/2023] [Accepted: 09/03/2023] [Indexed: 09/08/2023]
Abstract
Mechanical allodynia is a serious complication of painful diabetic neuropathy (PDN) with limited treatment options. The transient receptor potential canonical 5 (TRPC5) channel is a promising target in pain; however, its role in painful diabetic neuropathy has not yet been elucidated. In this study, we have investigated the role of TRPC5 channels using BTD [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4-benzothiadiazin-3-yl)-propanamide)],a potent TRPC5 activator and HC070, as TRPC5 channel inhibitor in rat model of PDN. In this study, streptozotocin was used to induce diabetes in male Sprague-Dawley rats. The alterations in mechanical and thermal pain thresholds, nerve functional deficits in diabetic animals were assessed by various behavioral and functional parameters.TRPC5 involvement was investigated by treating neuropathic rats with BTD, TRPC5 channel activator (1 and 3 mg/kg, i.p. for 14 days) and HC070, a TRPC5 channel inhibitor (1 and 3 mg/kg). BTD and HC070 effects in pain reduction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the lumbar spinal cord. BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated mechanical allodynia but not thermal hyposensation or nerve functional deficit in diabetic neuropathic rats. BTD treatment down-regulated TRPC5 expression by increasing the activity of protein kinase C. It also subsequently down-regulated the downstream pain markers (CAMKII, ERK) in the spinal cord. Additionally, a decrease in inflammatory cytokines (TNF-α, IL-6) also demonstrated BTD's potent anti-inflammatory properties in reducing mechanical allodynia. On the other hand, HC070 did not exert any beneficial effects on behavioural and nerve functional parameters. The study concludes that BTD ameliorated mechanical allodynia in a rat model of painful diabetic neuropathy not only through modulation of the TRPC5-CAMKII-ERK pathway but also through its anti-inflammatory and anti-apoptotic properties. Overall, BTD is a promising therapeutic molecule in the treatment of mechanical allodynia in painful diabetic neuropathy.
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Affiliation(s)
- Pratik Adhya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali), 160 062, Punjab, India
| | - Bhupesh Vaidya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali), 160 062, Punjab, India
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali), 160 062, Punjab, India.
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17
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Alsouhibani A, Speck P, Cole EF, Mustin DE, Li Y, Barron JR, Orenstein LAV, Harper DE. Quantitative Sensory Testing to Characterize Sensory Changes in Hidradenitis Suppurativa Skin Lesions. JAMA Dermatol 2023; 159:1102-1111. [PMID: 37702999 PMCID: PMC10500434 DOI: 10.1001/jamadermatol.2023.3243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 04/25/2023] [Indexed: 09/14/2023]
Abstract
Importance Pain is the most impactful symptom in patients with hidradenitis suppurativa (HS). Characterization of sensory profiles may improve understanding of pain mechanisms in HS and facilitate identification of effective pain management strategies. Objective To characterize somatosensory profiles in patients with HS at clinically affected and nonaffected sites compared with pain-free reference data. Design, Setting, and Participants This cross-sectional study was conducted at the Emory University Dermatology Clinic. It was hypothesized (1) that patients with HS would demonstrate hypersensitivity to pain in HS lesions and (2) that some patients would have sensory profiles consistent with complex pain mechanisms. Therefore, adults with dermatologist-diagnosed HS and at least 1 painful HS lesion at the time of testing were enrolled between September 10, 2020, and March 21, 2022. Patients with other diagnoses contributing to pain or neuropathy were excluded. Data analysis was conducted between March and April 2022. Exposure Quantitative sensory testing was performed on HS lesions and control skin according to a standardized protocol. Main Outcomes and Measures Quantitative sensory testing outcomes included innocuous thermal and mechanical sensitivity (cold, warmth, and light touch detection thresholds), noxious thermal and mechanical sensitivity (cold, heat, pinprick, and deep pressure pain thresholds and suprathreshold pinprick sensitivity), temporal summation of pinprick, paradoxical thermal sensations, and dynamic mechanical allodynia (pain upon light stroking of the skin). Sensitivity in HS lesions was compared with sensitivity in a control location (the hand) and in pain-free controls using t tests. Results This study included 20 participants with a median age of 35.5 (IQR, 30.0-46.5) years, the majority of whom were women (15 [75%]). In terms of race and ethnicity, 2 participants (10%) self-identified as Asian, 11 (55%) as Black, 6 (30%) as White, and 1 (5%) as more than 1 race or ethnicity. Compared with site-specific reference values from healthy, pain-free control participants, HS lesions were insensitive to innocuous cold and warmth, noxious heat, and light touch (t = -5.69, -10.20, -3.84, and 4.46, respectively; all P < .001). In contrast, HS lesions also demonstrated significant hypersensitivity to deep pressure pain (t = 8.36; P < .001) and cutaneous pinprick (t = 2.07; P = .046). Hypersensitivity to deep pressure pain was also observed in the control site (t = 5.85; P < .001). A subset of patients with HS displayed changes in pain processing that are often seen in neuropathic and nociplastic pain conditions, including hypersensitivity to repetitive pinprick (5 [26%]), paradoxical thermal sensations (3 [15%]), and pain upon light stroking of the skin (10 [50%]). Conclusions and Relevance The findings of this cross-sectional study suggest that HS involves local changes in the skin or its free nerve endings, possibly leading to peripheral neuropathy and alterations in the transduction of innocuous and noxious thermal and mechanical stimuli. For some patients, central nervous system changes in somatosensory processing may also occur, but confirmatory evidence is needed. Better understanding of neuropathic and nociplastic mechanisms in HS pain could lead to individually tailored treatments.
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Affiliation(s)
- Ali Alsouhibani
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia
- Department of Physical Therapy, College of Medical Rehabilitation, Qassim University, Buraydah, Saudi Arabia
| | - Patrick Speck
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
| | - Emily F. Cole
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
| | - Danielle E. Mustin
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
| | - Yiwen Li
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
| | - Jason R. Barron
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
| | | | - Daniel E. Harper
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia
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18
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Ramawad HA, Paridari P, Jabermoradi S, Gharin P, Toloui A, Safari S, Yousefifard M. Muscimol as a treatment for nerve injury-related neuropathic pain: a systematic review and meta-analysis of preclinical studies. Korean J Pain 2023; 36:425-440. [PMID: 37732408 PMCID: PMC10551397 DOI: 10.3344/kjp.23161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/27/2023] [Accepted: 08/01/2023] [Indexed: 09/22/2023] Open
Abstract
Background : Muscimol's quick onset and GABAergic properties make it a promising candidate for the treatment of pain. This systematic review and meta-analysis of preclinical studies aimed at summarizing the evidence regarding the efficacy of muscimol administration in the amelioration of nerve injury-related neuropathic pain. Methods : Two independent researchers performed the screening process in Medline, Embase, Scopus and Web of Science extracting data were extracted into a checklist designed according to the PRISMA guideline. A standardized mean difference (SMD [95% confidence interval]) was calculated for each. To assess the heterogeneity between studies, I2 and chi-square tests were utilized. In the case of heterogeneity, meta-regression and subgroup analyses were performed to identify the potential source. Results : Twenty-two articles met the inclusion criteria. Pooled data analysis showed that the administration of muscimol during the peak effect causes a significant reduction in mechanical allodynia (SMD = 1.78 [1.45-2.11]; P < 0.0001; I2 = 72.70%), mechanical hyperalgesia (SMD = 1.62 [1.28-1.96]; P < 0.0001; I2 = 40.66%), and thermal hyperalgesia (SMD = 2.59 [1.79-3.39]; P < 0.0001; I2 = 80.33%). This significant amendment of pain was observed at a declining rate from 15 minutes to at least 180 minutes post-treatment in mechanical allodynia and mechanical hyperalgesia, and up to 30 minutes in thermal hyperalgesia (P < 0 .0001). Conclusions : Muscimol is effective in the amelioration of mechanical allodynia, mechanical hyperalgesia, and thermal hyperalgesia, exerting its analgesic effects 15 minutes after administration for up to at least 3 hours.
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Affiliation(s)
- Hamzah Adel Ramawad
- Department of Emergency Medicine, NYC Health + Hospitals, Coney Island, NY, USA
| | - Parsa Paridari
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sajjad Jabermoradi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Pantea Gharin
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amirmohammad Toloui
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Saeed Safari
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmoud Yousefifard
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
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19
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Dourson AJ, Jankowski MP. Developmental impact of peripheral injury on neuroimmune signaling. Brain Behav Immun 2023; 113:156-165. [PMID: 37442302 PMCID: PMC10530254 DOI: 10.1016/j.bbi.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/01/2023] [Accepted: 07/05/2023] [Indexed: 07/15/2023] Open
Abstract
A peripheral injury drives neuroimmune interactions at the level of the injury and throughout the neuraxis. Understanding these systems will be beneficial in the pursuit to target persistent pain that involves both neural and immune components. In this review, we discuss the impact of injury on the development of neuroimmune signaling, along with data that suggest a possible cellular immune memory. We also discuss the parallel effects of injury in the nervous system and immune related areas including bone marrow, lymph node and central nervous system-related cells. Finally, we relate these findings to patient populations and current research that evaluates human tissue.
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Affiliation(s)
- Adam J Dourson
- Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
| | - Michael P Jankowski
- Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, United States; Pediatric Pain Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
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20
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Salama V, Youssef S, Xu T, Wahid KA, Chen J, Rigert J, Lee A, Hutcheson KA, Gunn B, Phan J, Garden AS, Frank SJ, Morrison W, Reddy JP, Spiotto MT, Naser MA, Dede C, He R, Mohamed AS, van Dijk LV, Lin R, Roldan CJ, Rosenthal DI, Fuller CD, Moreno AC. Temporal characterization of acute pain and toxicity kinetics during radiation therapy for head and neck cancer. A retrospective study. ORAL ONCOLOGY REPORTS 2023; 7:100092. [PMID: 38638130 PMCID: PMC11025722 DOI: 10.1016/j.oor.2023.100092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
Objectives Pain during Radiation Therapy (RT) for oral cavity/oropharyngeal cancer (OC/OPC) is a clinical challenge due to its multifactorial etiology and variable management. The objective of this study was to define complex pain profiles through temporal characterization of pain descriptors, physiologic state, and RT-induced toxicities for pain trajectories understanding. Materials and methods Using an electronic health record registry, 351 OC/OPC patients treated with RT from 2013 to 2021 were included. Weekly numeric scale pain scores, pain descriptors, vital signs, physician-reported toxicities, and analgesics were analyzed using linear mixed effect models and Spearman's correlation. Area under the pain curve (AUCpain) was calculated to measure pain burden over time. Results Median pain scores increased from 0 during the weekly visit (WSV)-1 to 5 during WSV-7. By WSV-7, 60% and 74% of patients reported mouth and throat pain, respectively, with a median pain score of 5. Soreness and burning pain peaked during WSV-6/7 (51%). Median AUCpain was 16% (IQR (9.3-23)), and AUCpain significantly varied based on gender, tumor site, surgery, drug use history, and pre-RT pain. A temporal increase in mucositis and dermatitis, declining mean bodyweight (-7.1%; P < 0.001) and mean arterial pressure (MAP) 6.8 mmHg; P < 0.001 were detected. Pulse rate was positively associated while weight and MAP were negatively associated with pain over time (P < 0.001). Conclusion This study provides insight on in-depth characterization and associations between dynamic pain, physiologic, and toxicity kinetics. Our findings support further needs of optimized pain control through temporal data-driven clinical decision support systems for acute pain management.
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Affiliation(s)
- Vivian Salama
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Sara Youssef
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Tianlin Xu
- Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Kareem A. Wahid
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jaime Chen
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jillian Rigert
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Anna Lee
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Katherine A. Hutcheson
- Department of Head and Neck Surgery, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Brandon Gunn
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jack Phan
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Adam S. Garden
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Steven J. Frank
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - William Morrison
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jay P. Reddy
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Michael T. Spiotto
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Mohamed A. Naser
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Cem Dede
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Renjie He
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Abdallah S.R. Mohamed
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Lisanne V. van Dijk
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, Medical Center Groningen, University of Groningen, Groningen, NL, USA
| | - Ruitao Lin
- Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Carlos J. Roldan
- Department of Pain Medicine, Division of Anesthesiology, Critical Care Medicine, and Pain Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - David I. Rosenthal
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Clifton D. Fuller
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Amy C. Moreno
- Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
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21
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Barcelon E, Chung S, Lee J, Lee SJ. Sexual Dimorphism in the Mechanism of Pain Central Sensitization. Cells 2023; 12:2028. [PMID: 37626838 PMCID: PMC10453375 DOI: 10.3390/cells12162028] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/01/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
It has long been recognized that men and women have different degrees of susceptibility to chronic pain. Greater recognition of the sexual dimorphism in chronic pain has resulted in increasing numbers of both clinical and preclinical studies that have identified factors and mechanisms underlying sex differences in pain sensitization. Here, we review sexually dimorphic pain phenotypes in various research animal models and factors involved in the sex difference in pain phenotypes. We further discuss putative mechanisms for the sexual dimorphism in pain sensitization, which involves sex hormones, spinal cord microglia, and peripheral immune cells. Elucidating the sexually dimorphic mechanism of pain sensitization may provide important clinical implications and aid the development of sex-specific therapeutic strategies to treat chronic pain.
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Affiliation(s)
- Ellane Barcelon
- Department of Physiology and Neuroscience, School of Dentistry, Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea; (E.B.); (S.C.); (J.L.)
| | - Seohyun Chung
- Department of Physiology and Neuroscience, School of Dentistry, Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea; (E.B.); (S.C.); (J.L.)
| | - Jaesung Lee
- Department of Physiology and Neuroscience, School of Dentistry, Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea; (E.B.); (S.C.); (J.L.)
- Department of Interdisciplinary Program in Neuroscience, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Sung Joong Lee
- Department of Physiology and Neuroscience, School of Dentistry, Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea; (E.B.); (S.C.); (J.L.)
- Department of Interdisciplinary Program in Neuroscience, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea
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22
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Garrity R, Arora N, Haque MA, Weis D, Trinh RT, Neerukonda SV, Kumari S, Cortez I, Ubogu EE, Mahalingam R, Tavares-Ferreira D, Price TJ, Kavelaars A, Heijnen CJ, Shepherd AJ. Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206 + myeloid cells. Brain Behav Immun 2023; 112:220-234. [PMID: 37315702 PMCID: PMC10527931 DOI: 10.1016/j.bbi.2023.06.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/26/2023] [Accepted: 06/10/2023] [Indexed: 06/16/2023] Open
Abstract
Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund's Adjuvant inflammatory pain model, we show that Pi16-/- mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain. In contrast to neuropathic pain models, we did not observe any changes in blood-nerve barrier permeability due to PI16 deletion. Instead, Pi16-/- mice display reduced macrophage density in the CFA-injected hindpaw. Furthermore, there was a significant bias toward CD206hi (anti-inflammatory) macrophages in the hindpaw and associated dorsal root ganglia. Following CFA, intrathecal depletion of CD206+ macrophages using mannosylated clodronate liposomes promoted sustained pain in Pi16-/- mice. Similarly, an IL-10 neutralizing antibody also promoted sustained CFA pain in the Pi16-/ when administered intrathecally. Collectively, our results point to fibroblast-derived PI16 mediating substantial differences in macrophage phenotype in the pain neuroaxis under conditions of inflammation. The co-expression of PI16 alongside fibroblast markers in human DRG raise the likelihood that a similar mechanism operates in human inflammatory pain states. Collectively, our findings may have implications for targeting fibroblast-immune cell crosstalk for the treatment of chronic pain.
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Affiliation(s)
- Rachelle Garrity
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Neha Arora
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Md Areeful Haque
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Drew Weis
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ronnie T Trinh
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sanjay V Neerukonda
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States
| | - Susmita Kumari
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ibdanelo Cortez
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Eroboghene E Ubogu
- Neuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, UK
| | - Rajasekaran Mahalingam
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Diana Tavares-Ferreira
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States
| | - Theodore J Price
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States
| | - Annemieke Kavelaars
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Cobi J Heijnen
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Psychological Sciences, Rice University, Houston, TX, United States
| | - Andrew J Shepherd
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
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23
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Cui H, Guo Z, Guo Z, Fan Z, Shen N, Qi X, Ma Y, Zhu Y, Wu X, Chen B, Xiang H. TMEM100 Regulates Neuropathic Pain by Reducing the Expression of Inflammatory Factors. Mediators Inflamm 2023; 2023:9151967. [PMID: 37469758 PMCID: PMC10352538 DOI: 10.1155/2023/9151967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/12/2022] [Accepted: 06/13/2023] [Indexed: 07/21/2023] Open
Abstract
There is no effective treatment for peripheral nerve injury-induced chronic neuropathic pain (NP), which profoundly impacts the quality of life of those affected. Transmembraneprotein100 (TMEM100) is considered to be a pain regulatory protein and is expressed in the dorsal root ganglion (DRG) of rats. However, the mechanism of pain regulation and the expression of TMEM100 following various peripheral nerve injuries are unclear. In this study, we constructed two pain models of peripheral nerve injury: tibial nerve injury (TNI) and chronic constriction injury (CCI). This study found that the Paw Withdrawal Mechanical Threshold (PWMT) and Paw Withdraw Thermal Latency (PWTL) of the rats in the two pain models decreased significantly, and the expression of TMEM100 in the DRG of two groups also decreased significantly. Furthermore, the decrease in the CCI group was more obvious than in the TNI group. There was no significant statistical significance (P > 0.05). We constructed an adeno-associated virus 6 (AAV6) vector expressing recombinant fluorescent TMEM100 protein and injected it into the sciatic nerve (SN) of two pain models: CCI and TNI. PWMT and PWTL were significantly increased in the two groups, along with the expression of TMEM100 in the spinal cord and DRG. It also significantly inhibited the activation of microglia, astrocytes, and several inflammatory mediators (TNF- α, IL-1 β, and IL-6). In summary, the results of this study suggested that TMEM100 might be a promising molecular strategy for the treatment of NP, and its anti-inflammatory effects might play an important role in pain relief.
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Affiliation(s)
- Huifei Cui
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Zhaoyang Guo
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
- Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhu Guo
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Zuoran Fan
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Nana Shen
- Department of Rehabilitation, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xiaoying Qi
- Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Yuanye Ma
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Youfu Zhu
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Xiaolin Wu
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Bohua Chen
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Hongfei Xiang
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
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24
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Li B, Guo J, Zhou X, Li W, Wang N, Cao R, Cui S. The emerging role of pyroptosis in neuropathic pain. Int Immunopharmacol 2023; 121:110562. [PMID: 37364324 DOI: 10.1016/j.intimp.2023.110562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/10/2023] [Accepted: 06/22/2023] [Indexed: 06/28/2023]
Abstract
Neuropathic pain caused by somatosensory system injuries is notoriously difficult to treat. Previous research has shown that neuroinflammation and cell death have been implicated in the pathophysiology of neuropathic pain. Pyroptosis is a form of programmed cell death associated with inflammatory processes, as it can enhance or sustain the inflammatory response by releasing pro-inflammatory cytokines. This review presents the current knowledge on pyroptosis and its underlying mechanisms, including the canonical and noncanonical pathways. Moreover, we discuss recent findings on the role of pyroptosis in neuropathic pain and its potential as a therapeutic target. In conclusion, this review highlights the potential significance of pyroptosis as a promising target for developing innovative therapies to treat neuropathic pain.
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Affiliation(s)
- Baolong Li
- Department of Hand and Foot Surgery, The Third Bethune Hospital of Jilin University, Changchun, China; Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin Province, Changchun, China
| | - Jin Guo
- Department of Hand and Foot Surgery, The Third Bethune Hospital of Jilin University, Changchun, China; Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin Province, Changchun, China
| | - Xiongyao Zhou
- Department of Hand and Foot Surgery, The Third Bethune Hospital of Jilin University, Changchun, China; Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin Province, Changchun, China
| | - Weizhen Li
- Department of Hand and Foot Surgery, The Third Bethune Hospital of Jilin University, Changchun, China; Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin Province, Changchun, China
| | - Ningning Wang
- Department of Hand and Foot Surgery, The Third Bethune Hospital of Jilin University, Changchun, China; Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin Province, Changchun, China
| | - Rangjuan Cao
- Department of Hand and Foot Surgery, The Third Bethune Hospital of Jilin University, Changchun, China; Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin Province, Changchun, China.
| | - Shusen Cui
- Department of Hand and Foot Surgery, The Third Bethune Hospital of Jilin University, Changchun, China; Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin Province, Changchun, China.
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Liu B, Wu W, Cui L, Zheng X, Li N, Zhang X, Duan G. A novel co-target of ACY1 governing plasma membrane translocation of SphK1 contributes to inflammatory and neuropathic pain. iScience 2023; 26:106989. [PMID: 37378314 PMCID: PMC10291574 DOI: 10.1016/j.isci.2023.106989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/31/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Previous studies validate that inhibiting sodium channel 1.8 (Nav1.8) effectively relieves inflammatory and neuropathic pain. However, Nav1.8 blockers have cardiac side effects in addition to analgesic effects. Here, we constructed a spinal differential protein expression profile using Nav1.8 knockout mice to screen common downstream proteins of Nav1.8 in inflammatory and neuropathic pain. We found that aminoacylase 1 (ACY1) expression was increased in wild-type mice compared to Nav1.8 knockout mice in both pain models. Moreover, spinal ACY1 overexpression induced mechanical allodynia in naive mice, while ACY1 suppression alleviated inflammatory and neuropathic pain. Further, ACY1 could interact with sphingosine kinase 1 and promote its membrane translocation, resulting in sphingosine-1-phosphate upregulation and the activation of glutamatergic neurons and astrocytes. In conclusion, ACY1 acts as a common downstream effector protein of Nav1.8 in inflammatory and neuropathic pain and could be a new and precise therapeutic target for chronic pain.
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Affiliation(s)
- Baowen Liu
- Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenyao Wu
- Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - LingLing Cui
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Anesthesiology, Wuhan third Hospital/Tongren Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Xuemei Zheng
- Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ningbo Li
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianwei Zhang
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangyou Duan
- Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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26
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Deal B, Phillips K, Crelli C, Janjic JM, Pollock JA. RNA-Seq Reveals Sex Differences in Gene Expression during Peripheral Neuropathic Inflammation and in Pain Relief from a COX-2 Inhibiting Theranostic Nanoemulsion. Int J Mol Sci 2023; 24:ijms24119163. [PMID: 37298117 DOI: 10.3390/ijms24119163] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/12/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
Given decades of neuroinflammatory pain research focused only on males, there is an urgent need to better understand neuroinflammatory pain in females. This, paired with the fact that currently there is no long-term effective treatment for neuropathic pain furthers the need to evaluate how neuropathic pain develops in both sexes and how it can be relieved. Here we show that chronic constriction injury of the sciatic nerve caused comparable levels of mechanical allodynia in both sexes. Using a COX-2 inhibiting theranostic nanoemulsion with increased drug loading, both sexes achieved similar reduction in mechanical hypersensitivity. Given that both sexes have improved pain behavior, we specifically explored differential gene expression between sexes in the dorsal root ganglia (DRG) during pain and relief. Total RNA from the DRG revealed a sexually dimorphic expression for injury and relief caused by COX-2 inhibition. Of note, both males and females experience increased expression of activating transcription factor 3 (Atf3), however, only the female DRG shows decreased expression following drug treatment. Alternatively, S100A8 and S100A9 expression appear to play a sex specific role in relief in males. The sex differences in RNA expression reveal that comparable behavior does not necessitate the same gene expression.
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Affiliation(s)
- Brooke Deal
- Department of Biological Sciences, School of Science & Engineering, Duquesne University, Pittsburgh, PA 15282, USA
- Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA 15282, USA
| | - Katherine Phillips
- Department of Biological Sciences, School of Science & Engineering, Duquesne University, Pittsburgh, PA 15282, USA
- Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA 15282, USA
| | - Caitlin Crelli
- Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA 15282, USA
- Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
| | - Jelena M Janjic
- Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA 15282, USA
- Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
| | - John A Pollock
- Department of Biological Sciences, School of Science & Engineering, Duquesne University, Pittsburgh, PA 15282, USA
- Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA 15282, USA
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27
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Dou X, Chen R, Yang J, Dai M, Long J, Sun S, Lin Y. The potential role of T-cell metabolism-related molecules in chronic neuropathic pain after nerve injury: a narrative review. Front Immunol 2023; 14:1107298. [PMID: 37266437 PMCID: PMC10229812 DOI: 10.3389/fimmu.2023.1107298] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 04/27/2023] [Indexed: 06/03/2023] Open
Abstract
Neuropathic pain is a common type of chronic pain, primarily caused by peripheral nerve injury. Different T-cell subtypes play various roles in neuropathic pain caused by peripheral nerve damage. Peripheral nerve damage can lead to co-infiltration of neurons and other inflammatory cells, thereby altering the cellular microenvironment and affecting cellular metabolism. By elaborating on the above, we first relate chronic pain to T-cell energy metabolism. Then we summarize the molecules that have affected T-cell energy metabolism in the past five years and divide them into two categories. The first category could play a role in neuropathic pain, and we explain their roles in T-cell function and chronic pain, respectively. The second category has not yet been involved in neuropathic pain, and we focus on how they affect T-cell function by influencing T-cell metabolism. By discussing the above content, this review provides a reference for studying the direct relationship between chronic pain and T-cell metabolism and searching for potential therapeutic targets for the treatment of chronic pain on the level of T-cell energy metabolism.
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Affiliation(s)
- Xiaoke Dou
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juexi Yang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Maosha Dai
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junhao Long
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shujun Sun
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pain, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Lin
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Aramini A, Bianchini G, Lillini S, Tomassetti M, Pacchiarotti N, Canestrari D, Cocchiaro P, Novelli R, Dragani MC, Palmerio F, Mattioli S, Bordignon S, d'Angelo M, Castelli V, d'Egidio F, Maione S, Luongo L, Boccella S, Cimini A, Brandolini L, Chierotti MR, Allegretti M. Ketoprofen, lysine and gabapentin co-crystal magnifies synergistic efficacy and tolerability of the constituent drugs: Pre-clinical evidences towards an innovative therapeutic approach for neuroinflammatory pain. Biomed Pharmacother 2023; 163:114845. [PMID: 37167730 DOI: 10.1016/j.biopha.2023.114845] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/29/2023] [Accepted: 05/04/2023] [Indexed: 05/13/2023] Open
Abstract
Chronic pain is an enormous public health concern, and its treatment is still an unmet medical need. Starting from data highlighting the promising effects of some nonsteroidal anti-inflammatory drugs in combination with gabapentin in pain treatment, we sought to combine ketoprofen lysine salt (KLS) and gabapentin to obtain an effective multimodal therapeutic approach for chronic pain. Using relevant in vitro models, we first demonstrated that KLS and gabapentin have supra-additive effects in modulating key pathways in neuropathic pain and gastric mucosal damage. To leverage these supra-additive effects, we then chemically combined the two drugs via co-crystallization to yield a new compound, a ternary drug-drug co-crystal of ketoprofen, lysine and gabapentin (KLS-GABA co-crystal). Physicochemical, biodistribution and pharmacokinetic studies showed that within the co-crystal, ketoprofen reaches an increased gastrointestinal solubility and permeability, as well as a higher systemic exposure in vivo compared to KLS alone or in combination with gabapentin, while both the constituent drugs have increased central nervous system permeation. These unique characteristics led to striking, synergistic anti-nociceptive and anti-inflammatory effects of KLS-GABA co-crystal, as well as significantly reduced spinal neuroinflammation, in translational inflammatory and neuropathic pain rat models, suggesting that the synergistic therapeutic effects of the constituent drugs are further boosted by the co-crystallization. Notably, while strengthening the therapeutic effects of ketoprofen, KLS-GABA co-crystal showed remarkable gastrointestinal tolerability in both inflammatory and chronic neuropathic pain rat models. In conclusion, these results allow us to propose KLS-GABA co-crystal as a new drug candidate with high potential clinical benefit-to-risk ratio for chronic pain treatment.
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Affiliation(s)
- Andrea Aramini
- R&D, Dompé Farmaceutici S.p.A, Via Campo di Pilel, 67100 L'Aquila, Italy.
| | - Gianluca Bianchini
- R&D, Dompé Farmaceutici S.p.A, Via Campo di Pilel, 67100 L'Aquila, Italy
| | - Samuele Lillini
- R&D, Dompé Farmaceutici S.p.A, Via De Amicis, 80131 Naples, Italy
| | - Mara Tomassetti
- R&D, Dompé Farmaceutici S.p.A, Via De Amicis, 80131 Naples, Italy
| | | | - Daniele Canestrari
- R&D, Dompé Farmaceutici S.p.A, Via Campo di Pilel, 67100 L'Aquila, Italy
| | | | - Rubina Novelli
- R&D, Dompé Farmaceutici S.p.A, Via S. Lucia, 20122 Milan, Italy
| | | | | | - Simone Mattioli
- R&D, Dompé Farmaceutici S.p.A, Via De Amicis, 80131 Naples, Italy
| | - Simone Bordignon
- Department of Chemistry and NIS Centre, University of Torino, 10124 Torino, Italy
| | - Michele d'Angelo
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy
| | - Francesco d'Egidio
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy
| | - Sabatino Maione
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Livio Luongo
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Serena Boccella
- R&D, Dompé Farmaceutici S.p.A, Via De Amicis, 80131 Naples, Italy
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy; Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Laura Brandolini
- R&D, Dompé Farmaceutici S.p.A, Via Campo di Pilel, 67100 L'Aquila, Italy
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Dainese P, Mahieu H, De Mits S, Wittoek R, Stautemas J, Calders P. Associations between markers of inflammation and altered pain perception mechanisms in people with knee osteoarthritis: a systematic review. RMD Open 2023; 9:rmdopen-2022-002945. [PMID: 37225282 DOI: 10.1136/rmdopen-2022-002945] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 04/01/2023] [Indexed: 05/26/2023] Open
Abstract
To provide an extensive review on the associations between knee inflammation and altered pain perception mechanisms in people with knee osteoarthritis (OA). MEDLINE, Web of Science, EMBASE and Scopus were searched up to 13 December 2022. We included articles reporting associations between knee inflammation (measured by effusion, synovitis, bone marrow lesions (BMLs) and cytokines) and signs of altered pain processing (assessed by quantitative sensory testing and/or questionnaire for neuropathic-like pain) in people with knee OA. Methodological quality was evaluated using the National Heart, Lung and Blood Institute Study Quality Assessment Tool. Level of evidence and strength of conclusion were determined using the Evidence-Based Guideline Development method. Nine studies were included, comprising of 1889 people with knee OA. Signs of greater effusion/synovitis may be positively associated with lower knee pain pressure threshold (PPT) and neuropathic-like pain. Current evidence could not establish an association between BMLs and pain sensitivity. Evidence on associations between inflammatory cytokines and pain sensitivity or neuropathic-like pain was conflicting. There are indications of a positive association between higher serum C reactive protein (CRP) levels and lower PPT and presence of temporal summation. Methodological quality varied from level C to A2. Signs of effusion/synovitis may be positively associated with neuropathic-like pain and pain sensitivity. There are indications of a possible positive association between serum CRP levels and pain sensitivity. Given the quality and the small amount of included studies, uncertainty remains. Future studies with adequate sample size and follow-up are needed to strengthen the level of evidence.PROSPERO registration number: CRD42022329245.
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Affiliation(s)
- Paolo Dainese
- Rehabilitation Sciences, Ghent University, Ghent, Belgium
| | - Hanne Mahieu
- Rehabilitation Sciences, Ghent University, Ghent, Belgium
| | - Sophie De Mits
- Rheumatology, University Hospital Ghent, Ghent, Belgium
- Smart Space, University Hospital Ghent, Ghent, Belgium
| | - Ruth Wittoek
- Rheumatology, University Hospital Ghent, Ghent, Belgium
- Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Jan Stautemas
- Rehabilitation Sciences, Ghent University, Ghent, Belgium
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Tsuchida R, Nishizawa D, Fukuda KI, Ichinohe T, Kano K, Kurano M, Ikeda K, Sumitani M. Genetic Polymorphisms of ENPP2 Are Possibly Associated with Pain Severity and Opioid Dose Requirements in Patients with Inflammatory Pain Conditions: Clinical Observation Study. Int J Mol Sci 2023; 24:ijms24086986. [PMID: 37108150 PMCID: PMC10139129 DOI: 10.3390/ijms24086986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/03/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.
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Affiliation(s)
- Rikuhei Tsuchida
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Hongo 7-3-1, Bunkyoku, Tokyo 113-8655, Japan
| | - Daisuke Nishizawa
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Kami Kitazawa 2-1-6, Setagayaku, Tokyo 156-0057, Japan
| | - Ken-Ichi Fukuda
- Department of Oral Health and Clinical Science, Tokyo Dental College, Kanda Misakichou 2-9-18, Chiyodaku, Tokyo 101-0061, Japan
| | - Tatsuya Ichinohe
- Department of Dental Anesthesiology, Tokyo Dental College, Kanda Misakichou 2-9-18, Chiyodaku, Tokyo 101-0061, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyoku, Tokyo 113-8655, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo Hospital, Hongo 7-3-1, Bunkyoku, Tokyo 113-8655, Japan
| | - Kazutaka Ikeda
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Kami Kitazawa 2-1-6, Setagayaku, Tokyo 156-0057, Japan
| | - Masahiko Sumitani
- Department of Pain and Palliative Medicine, The University of Tokyo Hospital, Hongo 7-3-1, Bunkyoku, Tokyo 113-8655, Japan
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31
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Mears L, Mears J. The pathophysiology, assessment, and management of acute pain. BRITISH JOURNAL OF NURSING (MARK ALLEN PUBLISHING) 2023; 32:58-65. [PMID: 36715521 DOI: 10.12968/bjon.2023.32.2.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
This article reviews the pathophysiology and treatment of acute pain. Two definitions of pain are considered, along with the International Association for the Study of Pain taxonomy for nociceptive, neuropathic and nociplastic pain. The mechanisms of acute and neuropathic pain are considered. Methods of assessment are discussed followed by the pharmacological management of both nociceptive and neuropathic pain.
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Affiliation(s)
- Lyndsey Mears
- Senior Lecturer, College of Nursing, Midwifery and Healthcare, University of West London
| | - John Mears
- Hourly Paid Lecturer, College of Nursing, Midwifery and Healthcare, University of West London
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32
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Ye F, Du L, Huang W, Wang S. Shared Genetic Regulatory Networks Contribute to Neuropathic and Inflammatory Pain: Multi-Omics Systems Analysis. Biomolecules 2022; 12:1454. [PMID: 36291662 PMCID: PMC9599593 DOI: 10.3390/biom12101454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 09/27/2022] [Accepted: 10/07/2022] [Indexed: 11/17/2022] Open
Abstract
The mechanisms of chronic pain are complex, and genetic factors play an essential role in the development of chronic pain. Neuropathic pain (NP) and inflammatory pain (IP) are two primary components of chronic pain. Previous studies have uncovered some common biological processes in NP and IP. However, the shared genetic mechanisms remained poorly studied. We utilized multi-omics systematic analyses to investigate the shared genetic mechanisms of NP and IP. First, by integrating several genome-wide association studies (GWASs) with multi-omics data, we revealed the significant overlap of the gene co-expression modules in NP and IP. Further, we uncovered the shared biological pathways, including the previously reported mitochondrial electron transport and ATP metabolism, and stressed the role of genetic factors in chronic pain with neurodegenerative diseases. Second, we identified 24 conservative key drivers (KDs) contributing to NP and IP, containing two well-established pain genes, IL1B and OPRM1, and some novel potential pain genes, such as C5AR1 and SERPINE1. The subnetwork of those KDs highlighted the processes involving the immune system. Finally, gene expression analysis of the KDs in mouse models underlined two of the KDs, SLC6A15 and KCNQ5, with unidirectional regulatory functions in NP and IP. Our study provides strong evidence to support the current understanding of the shared genetic regulatory networks underlying NP and IP and potentially benefit the future common therapeutic avenues for chronic pain.
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Affiliation(s)
- Fang Ye
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Li Du
- Vitalant Research Institute, San Francisco, CA 94118, USA
- Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA
| | - Wenqi Huang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Sheng Wang
- Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA 94143, USA
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33
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Biswas P, Shahnaz M, Akhter M, Ripa AP, Ali T, Rafiq K. Effects of Azadirachta indica on neuropathic pain induced by chronic constriction injury to sciatic nerve of Wistar rat. J Adv Vet Anim Res 2022; 9:359-368. [PMID: 36382046 PMCID: PMC9597922 DOI: 10.5455/javar.2022.i603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 07/13/2022] [Accepted: 07/13/2022] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVE The research was designed to assess the consequences of Azadirachta indica aqueous leaf extract (AILE) on neuropathic pain in Wister rats and the role of the ATP-dependent potassium channel (KATP) as an underlying mechanism. MATERIALS AND METHODS This experimental layout was conducted on Wistar rats (n = 120) having 150 to 200 gm of body weight. On the foundation of the experimental design, rats were divided into group I (normal saline, 5 ml/kg/body weight) and group II (sham surgery and treatment with NS), group III [chronic constriction injury (CCI) in the sciatic nerve; and treated with NS], group IV (CCI and treated with AILE 400 mg/kg body weight), Group V (CCI, pretreated with Glibenclamide 15 mg/kg followed by treated with AILE 400 mg/kg). All the treatments were given once daily for a consecutive 21 days via the oral route, except Glibenclamide. Glibenclamide was given once through the intraperitoneal route on the day of the experiment. RESULTS Based on the neuropathic pain evaluation test, all groups were again sub-divided into subgroup "a" (walking tract analysis), "b" (cold tail immersion test), "c" (Von Frey test), and "d" (hot plate test). AILE showed a significantly higher sciatic functional index (p < 0.05) in walking track analysis, tail flick latency (p ≤ 0.05) in the cold tail immersion test, and paw withdrawal threshold (p ≤ 0.05) in the Von Frey test compared to CCI control. In addition, a nonsignificant difference in all these above-mentioned variables between the rats with CCI plus AILE and the CCI plus AILE plus glibenclamide group indicated that the KATP channel was not involved in the beneficial analgesic effects of AILE. CONCLUSIONS The outcome of the present study indicates that AILE prevented worsening of neuropathic pain after chronic constriction injury in the sciatic nerve of Wistar rats in which the KATP channel was not involved.
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Affiliation(s)
- Parijat Biswas
- Department of Physiology, Ashiyan Medical College Hospital, Dhaka, Bangladesh
| | - Monira Shahnaz
- Department of Physiology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | - Arifa Parvin Ripa
- Department of Pharmacology, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Taskina Ali
- Department of Physiology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Kazi Rafiq
- Department of Pharmacology, Bangladesh Agricultural University, Mymensingh, Bangladesh
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34
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Micheli L, Toti A, Lucarini E, Ferrara V, Ciampi C, Olivero G, Pittaluga A, Mattoli L, Pelucchini C, Burico M, Lucci J, Carrino D, Pacini A, Pallanti S, Di Cesare Mannelli L, Ghelardini C. Efficacy of a vegetal mixture composed of Zingiber officinale, Echinacea purpurea, and Centella asiatica in a mouse model of neuroinflammation: In vivo and ex vivo analysis. Front Nutr 2022; 9:887378. [PMID: 36118773 PMCID: PMC9472218 DOI: 10.3389/fnut.2022.887378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/25/2022] [Indexed: 12/04/2022] Open
Abstract
Experimental evidence suggests that neuroinflammation is a key pathological event of many diseases affecting the nervous system. It has been well recognized that these devastating illnesses (e.g., Alzheimer’s, Parkinson’s, depression, and chronic pain) are multifactorial, involving many pathogenic mechanisms, reason why pharmacological treatments are unsatisfactory. The purpose of this study was to evaluate the efficacy of a vegetal mixture capable of offering a multiple approach required to manage the multifactoriality of neuroinflammation. A mixture composed of Zingiber officinale (150 mg kg−1), Echinacea purpurea (20 mg kg−1), and Centella asiatica (200 mg kg−1) was tested in a mouse model of systemic neuroinflammation induced by lipopolysaccharide (LPS, 1 mg kg−1). Repeated treatment with the vegetal mixture was able to completely counteract thermal and mechanical allodynia as reported by the Cold plate and von Frey tests, respectively, and to reduce the motor impairments as demonstrated by the Rota rod test. Moreover, the mixture was capable of neutralizing the memory loss in the Passive avoidance test and reducing depressive-like behavior in the Porsolt test, while no efficacy was shown in decreasing anhedonia as demonstrated by the Sucrose preference test. Finally, LPS stimulation caused a significant increase in the activation of glial cells, of the central complement proteins and of inflammatory cytokines in selected regions of the central nervous system (CNS), which were rebalanced in animals treated with the vegetal mixture. In conclusion, the vegetal mixture tested thwarted the plethora of symptoms evoked by LPS, thus being a potential candidate for future investigations in the context of neuroinflammation.
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Affiliation(s)
- Laura Micheli
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
- *Correspondence: Laura Micheli,
| | - Alessandra Toti
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Elena Lucarini
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Valentina Ferrara
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Clara Ciampi
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Guendalina Olivero
- Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Anna Pittaluga
- Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Luisa Mattoli
- Innovation and Medical Science Division, Aboca SpA Società Agricola, Sansepolcro, Italy
| | - Caroline Pelucchini
- Innovation and Medical Science Division, Aboca SpA Società Agricola, Sansepolcro, Italy
| | - Michela Burico
- Innovation and Medical Science Division, Aboca SpA Società Agricola, Sansepolcro, Italy
| | - Jacopo Lucci
- Innovation and Medical Science Division, Aboca SpA Società Agricola, Sansepolcro, Italy
| | - Donatello Carrino
- Anatomy and Histology Section, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessandra Pacini
- Anatomy and Histology Section, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Stefano Pallanti
- Psychiatry Section, Department of Neurofarba, University of Florence, Florence, Italy
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, New York, NY, United States
- Institute of Neuroscience, Florence, Italy
| | - Lorenzo Di Cesare Mannelli
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Carla Ghelardini
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
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Turnaturi R, Chiechio S, Pasquinucci L, Spoto S, Costanzo G, Dichiara M, Piana S, Grasso M, Amata E, Marrazzo A, Parenti C. Novel N-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27165135. [PMID: 36014375 PMCID: PMC9413390 DOI: 10.3390/molecules27165135] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/04/2022] [Accepted: 08/07/2022] [Indexed: 11/30/2022]
Abstract
Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σ1R) antagonism, could be an opioid adjuvant strategy. The in vitro σ1R and σ2R profiles of previous synthesized MOR/DOR agonists (−)-2R/S-LP2 (1), (−)-2R-LP2 (2), and (−)-2S-LP2 (3) were assayed. To investigate the pivotal role of N-normetazocine stereochemistry, we also synthesized the (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) compounds. (−)-2R/S-LP2 (1), (−)-2R-LP2 (2), and (−)-2S-LP2 (3) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (−)-2S-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2R/S-LP2 (7), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed N-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.
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Affiliation(s)
- Rita Turnaturi
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Santina Chiechio
- Department of Drug and Health Sciences, Section of Pharmacology and Toxicology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Oasi Research Institute—IRCCS, 94018 Troina, Italy
| | - Lorella Pasquinucci
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Correspondence: ; Tel.: +39-095-738-4273
| | - Salvatore Spoto
- Department of Drug and Health Sciences, Section of Pharmacology and Toxicology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Giuliana Costanzo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97, 95123 Catania, Italy
| | - Maria Dichiara
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Silvia Piana
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | | | - Emanuele Amata
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Agostino Marrazzo
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Carmela Parenti
- Department of Drug and Health Sciences, Section of Pharmacology and Toxicology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
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36
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Diaz MM, Caylor J, Strigo I, Lerman I, Henry B, Lopez E, Wallace MS, Ellis RJ, Simmons AN, Keltner JR. Toward Composite Pain Biomarkers of Neuropathic Pain-Focus on Peripheral Neuropathic Pain. FRONTIERS IN PAIN RESEARCH 2022; 3:869215. [PMID: 35634449 PMCID: PMC9130475 DOI: 10.3389/fpain.2022.869215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/21/2022] [Indexed: 01/09/2023] Open
Abstract
Chronic pain affects ~10-20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.
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Affiliation(s)
- Monica M. Diaz
- Department of Neurology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States
| | - Jacob Caylor
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Irina Strigo
- Department of Psychiatry, San Francisco Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Imanuel Lerman
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Brook Henry
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
| | - Eduardo Lopez
- Department of Psychiatry, San Francisco Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Mark S. Wallace
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Ronald J. Ellis
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Alan N. Simmons
- Department of Psychiatry, San Diego & Center of Excellence in Stress and Mental Health, Veteran Affairs Health Care System, University of California, San Diego, San Diego, CA, United States
| | - John R. Keltner
- Department of Psychiatry, San Diego & San Diego VA Medical Center, University of California, San Diego, San Diego, CA, United States
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Seidel MF, Hügle T, Morlion B, Koltzenburg M, Chapman V, MaassenVanDenBrink A, Lane NE, Perrot S, Zieglgänsberger W. Neurogenic inflammation as a novel treatment target for chronic pain syndromes. Exp Neurol 2022; 356:114108. [PMID: 35551902 DOI: 10.1016/j.expneurol.2022.114108] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/01/2022] [Accepted: 05/03/2022] [Indexed: 11/24/2022]
Abstract
Chronic pain syndrome is a heterogeneous group of diseases characterized by several pathological mechanisms. One in five adults in Europe may experience chronic pain. In addition to the individual burden, chronic pain has a significant societal impact because of work and school absences, loss of work, early retirement, and high social and healthcare costs. Several anti-inflammatory treatments are available for patients with inflammatory or autoimmune diseases to control their symptoms, including pain. However, patients with degenerative chronic pain conditions, some with 10-fold or more elevated incidence relative to these manageable diseases, have few long-term pharmacological treatment options, limited mainly to non-steroidal anti-inflammatory drugs or opioids. For this review, we performed multiple PubMed searches using keywords such as "pain," "neurogenic inflammation," "NGF," "substance P," "nociception," "BDNF," "inflammation," "CGRP," "osteoarthritis," and "migraine." Many treatments, most with limited scientific evidence of efficacy, are available for the management of chronic pain through a trial-and-error approach. Although basic science and pre-clinical pain research have elucidated many biomolecular mechanisms of pain and identified promising novel targets, little of this work has translated into better clinical management of these conditions. This state-of-the-art review summarizes concepts of chronic pain syndromes and describes potential novel treatment strategies.
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Affiliation(s)
- Matthias F Seidel
- Department of Rheumatology, Spitalzentrum Biel-Centre Hospitalier Bienne, 2501 Biel-Bienne, Switzerland.
| | - Thomas Hügle
- Department of Rheumatology, University Hospital Lausanne, 1011 Lausanne, Switzerland
| | - Barton Morlion
- The Leuven Center for Algology and Pain Management, University of Leuven, Leuven, Belgium
| | - Martin Koltzenburg
- Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, United Kingdom; Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, London, United Kingdom
| | - Victoria Chapman
- Pain Centre Versus Arthritis, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom
| | - Antoinette MaassenVanDenBrink
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Nancy E Lane
- Center for Musculoskeletal Health, University of California Davis School of Medicine, Sacramento, CA, USA; Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Serge Perrot
- Unité INSERM U987, Hôpital Ambroise Paré, Paris Descartes University, Boulogne Billancourt, France; Centre d'Evaluation et Traitement de la Douleur, Hôpital Cochin, Paris Descartes University, Paris, France
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38
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Dedek A, Xu J, Lorenzo LÉ, Godin AG, Kandegedara CM, Glavina G, Landrigan JA, Lombroso PJ, De Koninck Y, Tsai EC, Hildebrand ME. Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain. Brain 2022; 145:1124-1138. [PMID: 35323848 PMCID: PMC9050559 DOI: 10.1093/brain/awab408] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/03/2021] [Accepted: 10/15/2021] [Indexed: 12/23/2022] Open
Abstract
The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.
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Affiliation(s)
- Annemarie Dedek
- Department of Neuroscience, Carleton University, K1S 5B6 Ontario, Canada.,Neuroscience Program, Ottawa Hospital Research Institute, K1Y 4M9 Ontario, Canada
| | - Jian Xu
- Child Study Center, Yale University School of Medicine, New Haven, CT 06519, USA
| | | | - Antoine G Godin
- CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec G1E 1T2, Canada.,Department of Psychiatry and Neuroscience, Université Laval, Quebec G1V 0A6, Canada
| | - Chaya M Kandegedara
- Department of Neuroscience, Carleton University, K1S 5B6 Ontario, Canada.,Neuroscience Program, Ottawa Hospital Research Institute, K1Y 4M9 Ontario, Canada
| | - Geneviève Glavina
- CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec G1E 1T2, Canada
| | | | - Paul J Lombroso
- Child Study Center, Yale University School of Medicine, New Haven, CT 06519, USA
| | - Yves De Koninck
- CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec G1E 1T2, Canada.,Department of Psychiatry and Neuroscience, Université Laval, Quebec G1V 0A6, Canada
| | - Eve C Tsai
- Neuroscience Program, Ottawa Hospital Research Institute, K1Y 4M9 Ontario, Canada.,Brain and Mind Research Institute, University of Ottawa, Ontario K1N 6N5, Canada.,Department of Surgery, Division of Neurosurgery, The Ottawa Hospital, Ontario K1Y 4E9, Canada
| | - Michael E Hildebrand
- Department of Neuroscience, Carleton University, K1S 5B6 Ontario, Canada.,Neuroscience Program, Ottawa Hospital Research Institute, K1Y 4M9 Ontario, Canada
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39
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A nigra-subthalamic circuit is involved in acute and chronic pain states. Pain 2022; 163:1952-1966. [PMID: 35082251 DOI: 10.1097/j.pain.0000000000002588] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/18/2022] [Indexed: 11/25/2022]
Abstract
ABSTRACT The basal ganglia modulate somatosensory pain pathways but it is unclear whether a common circuit exists to mitigate hyperalgesia in pain states induced by peripheral nociceptive stimuli. As a key output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr) may be a candidate for this role. To test this possibility, we optogenetically modulated SNr GABAergic neurons and examined pain thresholds in freely behaving male mice in inflammatory and neuropathic pain states as well as comorbid depression in chronic pain. We observed that stimulation of either SNr GABAergic neurons or their projections to the subthalamic nucleus (STN) significantly alleviated nociceptive responses in all pain states on the contralateral side and comorbid depression in chronic pain, and that this analgesic effect was eliminated when SNr-STN GABAergic projection was blocked. However, SNr modulation did not affect baseline pain thresholds. We also found that SNr-STN GABAergic projection was attenuated in pain states, resulting in disinhibition of STN neurons. Thus, impairment of the SNr-STN GABAergic circuit may be a common pathophysiology for the maintenance of hyperalgesia in both inflammatory and neuropathic pain states and the comorbid depression in chronic pain; compensating this circuit has potential to effectively treat related pain conditions.
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40
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Jensen KL, Noes-Holt G, Sørensen AT, Madsen KL. A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain. Front Cell Neurosci 2021; 15:750902. [PMID: 34975407 PMCID: PMC8714954 DOI: 10.3389/fncel.2021.750902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 11/25/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic pain is a major healthcare problem that impacts one in five adults across the globe. Current treatment is compromised by dose-limiting side effects including drowsiness, apathy, fatigue, loss of ability to function socially and professionally as well as a high abuse liability. Most of these side effects result from broad suppression of excitatory neurotransmission. Chronic pain states are associated with specific changes in the efficacy of synaptic transmission in the pain pathways leading to amplification of non-noxious stimuli and spontaneous pain. Consequently, a reversal of these specific changes may pave the way for the development of efficacious pain treatment with fewer side effects. We have recently described a high-affinity, bivalent peptide TAT-P4-(C5)2, enabling efficient targeting of the neuronal scaffold protein, PICK1, a key protein in mediating chronic pain sensitization. In the present study, we demonstrate that in an inflammatory pain model, the peptide does not only relieve mechanical allodynia by targeting PICK1 involved in central sensitization, but also by peripheral actions in the inflamed paw. Further, we assess the effects of the peptide on novelty-induced locomotor activity, abuse liability, and memory performance without identifying significant side effects.
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Affiliation(s)
- Kathrine Louise Jensen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Kenneth Lindegaard Madsen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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41
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Jansen LAR, Forster LA, Smith XL, Rubaharan M, Murphy AZ, Baro DJ. Changes in peripheral HCN2 channels during persistent inflammation. Channels (Austin) 2021; 15:165-179. [PMID: 33423595 PMCID: PMC7808421 DOI: 10.1080/19336950.2020.1870086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 02/01/2023] Open
Abstract
Nociceptor sensitization following nerve injury or inflammation leads to chronic pain. An increase in the nociceptor hyperpolarization-activated current, Ih, is observed in many models of pathological pain. Pharmacological blockade of Ih prevents the mechanical and thermal hypersensitivity that occurs during pathological pain. Alterations in the Hyperpolarization-activated Cyclic Nucleotide-gated ion channel 2 (HCN2) mediate Ih-dependent thermal and mechanical hyperalgesia. Limited knowledge exists regarding the nature of these changes during chronic inflammatory pain. Modifications in HCN2 expression and post-translational SUMOylation have been observed in the Complete Freund's Adjuvant (CFA) model of chronic inflammatory pain. Intra-plantar injection of CFA into the rat hindpaw induces unilateral hyperalgesia that is sustained for up to 14 days following injection. The hindpaw is innervated by primary afferents in lumbar DRG, L4-6. Adjustments in HCN2 expression and SUMOylation have been well-documented for L5 DRG during the first 7 days of CFA-induced inflammation. Here, we examine bilateral L4 and L6 DRG at day 1 and day 3 post-CFA. Using L4 and L6 DRG cryosections, HCN2 expression and SUMOylation were measured with immunohistochemistry and proximity ligation assays, respectively. Our findings indicate that intra-plantar injection of CFA elicited a bilateral increase in HCN2 expression in L4 and L6 DRG at day 1, but not day 3, and enhanced HCN2 SUMOylation in ipsilateral L6 DRG at day 1 and day 3. Changes in HCN2 expression and SUMOylation were transient over this time course. Our study suggests that HCN2 is regulated by multiple mechanisms during CFA-induced inflammation.
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Affiliation(s)
- L-A. R. Jansen
- Department of Biology, Georgia State University, Atlanta, Georgia
| | - L. A. Forster
- Department of Biology, Georgia State University, Atlanta, Georgia
- Neuroscience Institute, Georgia State University, Atlanta, Georgia
| | - X. L. Smith
- Department of Biology, Georgia State University, Atlanta, Georgia
| | - M. Rubaharan
- Neuroscience Institute, Georgia State University, Atlanta, Georgia
| | - A. Z. Murphy
- Neuroscience Institute, Georgia State University, Atlanta, Georgia
| | - D. J. Baro
- Department of Biology, Georgia State University, Atlanta, Georgia
- Neuroscience Institute, Georgia State University, Atlanta, Georgia
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42
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Bernard Healey SA, Scholtes I, Abrahams M, McNaughton PA, Menon DK, Lee MC. Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain. Pain Rep 2021; 6:e967. [PMID: 34712888 PMCID: PMC8547924 DOI: 10.1097/pr9.0000000000000967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/23/2021] [Accepted: 09/11/2021] [Indexed: 11/25/2022] Open
Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel receptors mediate neuropathic pain in preclinical models. Here, exploratory analysis reveals a dose-dependent reduction in pain with HCN blockade in patients with neuropathic pain. Introduction: Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels mediate repetitive action potential firing in the heart and nervous system. The HCN2 isoform is expressed in nociceptors, and preclinical studies suggest a critical role in neuropathic pain. Ivabradine is a nonselective HCN blocker currently available for prescription for cardiac indications. Mouse data suggest that ivabradine in high concentrations is equianalgesic with gabapentin. We sought to translate these findings to patients with chronic peripheral neuropathic pain. Objectives: We sought to translate these findings to patients with chronic peripheral neuropathic pain. Methods: We adopted an open-label design, administering increasing doses of ivabradine to target a heart rate of 50 to 60 BPM, up to a maximum of 7.5 mg twice daily. All participants scored their pain on an 11-point numerical rating scale (NRS). Results: Seven (7) participants received the drug and completed the study. There was no significant treatment effect on the primary endpoint, the difference between the mean score at baseline and at maximum dosing (mean reduction = 0.878, 95% CI = −2.07 to 0.31, P = 0.1). Exploratory analysis using linear mixed models, however, revealed a highly significant correlation between ivabradine dose and pain scores (χ2(1) = 74.6, P < 0.001), with a reduction of 0.12 ± 0.01 (SEM) NRS points per milligram. The 2 participants with painful diabetic neuropathy responded particularly well. Conclusion: This suggests that ivabradine may be efficacious at higher doses, particularly in patients with diabetic neuropathic pain. Importantly, participants reported no adverse effects. These data suggest that ivabradine, a peripherally restricted drug (devoid of central nervous system side effects), is well tolerated in patients with chronic neuropathic pain. Ivabradine is now off-patent, and its analgesic potential merits further investigation in clinical trials.
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Affiliation(s)
| | - Ingrid Scholtes
- Division of Anaesthesia, University of Cambridge, Cambridge, United Kingdom
| | - Mark Abrahams
- Pain Service, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom
| | - Peter A McNaughton
- Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
| | - David K Menon
- Division of Anaesthesia, University of Cambridge, Cambridge, United Kingdom
| | - Michael C Lee
- Division of Anaesthesia, University of Cambridge, Cambridge, United Kingdom
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43
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Guha S, Ferrie RP, Ghimire J, Ventura CR, Wu E, Sun L, Kim SY, Wiedman GR, Hristova K, Wimley WC. Applications and evolution of melittin, the quintessential membrane active peptide. Biochem Pharmacol 2021; 193:114769. [PMID: 34543656 DOI: 10.1016/j.bcp.2021.114769] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
Melittin, the main venom component of the European Honeybee, is a cationic linear peptide-amide of 26 amino acid residues with the sequence: GIGAVLKVLTTGLPALISWIKRKRQQ-NH2. Melittin binds to lipid bilayer membranes, folds into amphipathic α-helical secondary structure and disrupts the permeability barrier. Since melittin was first described, a remarkable array of activities and potential applications in biology and medicine have been described. Melittin is also a favorite model system for biophysicists to study the structure, folding and function of peptides and proteins in membranes. Melittin has also been used as a template for the evolution of new activities in membranes. Here we overview the rich history of scientific research into the many activities of melittin and outline exciting future applications.
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Affiliation(s)
- Shantanu Guha
- University of Texas Health Science Center at Houston, Department of Microbiology and Molecular Genetics, Houston, TX, USA
| | - Ryan P Ferrie
- Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA
| | - Jenisha Ghimire
- Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA
| | - Cristina R Ventura
- Seton Hall University, Department of Chemistry and Biochemistry, South Orange, NJ, USA
| | - Eric Wu
- Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA
| | - Leisheng Sun
- Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA
| | - Sarah Y Kim
- Duke University, Department of Biomedical Engineering, Durham, NC, USA
| | - Gregory R Wiedman
- Seton Hall University, Department of Chemistry and Biochemistry, South Orange, NJ, USA
| | - Kalina Hristova
- Johns Hopkins University, Department of Materials Science and Engineering, Baltimore, MD, USA.
| | - Wimley C Wimley
- University of Texas Health Science Center at Houston, Department of Microbiology and Molecular Genetics, Houston, TX, USA.
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Hsu YC, Ma KH, Guo SL, Lin BF, Tsai CS, Yeh CC. The Occurrence of Pain-Induced Depression Is Different between Rat Models of Inflammatory and Neuropathic Pain. J Clin Med 2021; 10:jcm10174016. [PMID: 34501464 PMCID: PMC8432452 DOI: 10.3390/jcm10174016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/18/2021] [Accepted: 09/02/2021] [Indexed: 12/15/2022] Open
Abstract
Various pain conditions may be associated with depressed mood. However, the effect of inflammatory or neuropathic pain on depression-like behavior and its associated time frame has not been well established in rat models. This frontward study investigated the differences in pain behavior, depression-like behavior, and serotonin transporter (SERT) distribution in the brain between rats subjected to spared nerve injury (SNI)-induced neuropathic pain or complete Freund’s adjuvant (CFA)-induced inflammatory pain. A dynamic plantar aesthesiometer and an acetone spray test were used to evaluate mechanical and cold allodynia responses, and depression-like behavior was examined using a forced swimming test and sucrose preference test. We also investigated SERT expression by using positron emission tomography. We found that the inflammation-induced pain was less severe than neuropathic pain from days 3 to 28 after induced pain; however, the CFA-injected rats exhibited more noticeable depression-like behavior and had significantly reduced SERT expression in the brain regions (thalamus and striatum) at an early stage (on days 14, 21, and 28 in two groups of CFA-injected rats versus day 28 in SNI rats). We speculated that not only the pain response after initial injury but also the subsequent neuroinflammation may have been the crucial factors influencing depression-like behavior in rats.
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Affiliation(s)
- Yung-Chi Hsu
- Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (Y.-C.H.); (S.-L.G.); (B.-F.L.)
- Integrated Pain Management Center, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Kuo-Hsing Ma
- Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan;
| | - Shu-Lin Guo
- Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (Y.-C.H.); (S.-L.G.); (B.-F.L.)
- Department of Anesthesiology, Cathay General Hospital, Taipei 106, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Bo-Feng Lin
- Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (Y.-C.H.); (S.-L.G.); (B.-F.L.)
- Integrated Pain Management Center, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Chien-Sung Tsai
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan;
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei 114, Taiwan
| | - Chun-Chang Yeh
- Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (Y.-C.H.); (S.-L.G.); (B.-F.L.)
- Integrated Pain Management Center, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Correspondence: ; Tel.: +886-2-8792-3311 (ext. 17051); Fax: +886-2-8792-7127
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Chuinsiri N, Edwards D, Telezhkin V, Nile CJ, Van der Cruyssen F, Durham J. Exploring the roles of neuropeptides in trigeminal neuropathic pain: A systematic review and narrative synthesis of animal studies. Arch Oral Biol 2021; 130:105247. [PMID: 34454375 DOI: 10.1016/j.archoralbio.2021.105247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/02/2021] [Accepted: 08/22/2021] [Indexed: 12/09/2022]
Abstract
OBJECTIVE This systematic review aims to explore the changes in expression of neuropeptides and/or their receptors following experimental trigeminal neuropathic pain in animals. DESIGN MEDLINE, Embase, and Scopus were searched for publications up to 31st March 2021. Study selection and data extraction were completed by two independent reviewers based on the eligibility criteria. The quality of articles was judged based on the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk-of-bias tool. RESULTS A total of 19 studies satisfied the eligibility criteria and were included for narrative synthesis. Methods of trigeminal neuropathic pain induction were nerve ligation, nerve compression/crush, nerve transection and dental pulp injury. Animal behaviours used for pain verification were evoked responses to mechanical and thermal stimuli. Non-evoked behaviours, including vertical exploration, grooming and food consumption, were also employed in some studies. Calcitonin gene-related peptide (CGRP) and substance P were the most frequently reported neuropeptides. Overall, unclear to high risk of bias was identified in the included studies. CONCLUSIONS Limited evidence has suggested the pro-nociceptive role of CGRP in trigeminal neuropathic pain. In order to further translational pain research, animal models of trigeminal neuropathic pain and pain validation methods need to be optimised. Complete reporting of future studies based on available guidelines to improve confidence in research is encouraged.
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Affiliation(s)
- Nontawat Chuinsiri
- School of Dental Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
| | - David Edwards
- School of Dental Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Vsevolod Telezhkin
- School of Dental Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Christopher J Nile
- School of Dental Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Fréderic Van der Cruyssen
- Department of Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium; OMFS-IMPATH Research Group, Department of Imaging and Pathology, Faculty of Medicine, University Leuven, Leuven, Belgium
| | - Justin Durham
- School of Dental Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Tran PV, Johns ME, McAdams B, Abrahante JE, Simone DA, Banik RK. Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain. Mol Pain 2021; 16:1744806920956480. [PMID: 32909881 PMCID: PMC7493244 DOI: 10.1177/1744806920956480] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To develop non-opioid therapies for postoperative incisional pain, we must understand its underlying molecular mechanisms. In this study, we assessed global gene expression changes in dorsal root ganglia neurons in a model of incisional pain to identify pertinent molecular pathways. Male, Sprague-Dawley rats underwent infiltration of 1% capsaicin or vehicle into the plantar hind paw (n = 6-9/group) 30 min before plantar incision. Twenty-four hours after incision or sham (control) surgery, lumbar L4-L6 dorsal root ganglias were collected from rats pretreated with vehicle or capsaicin. RNA was isolated and sequenced by next generation sequencing. The genes were then annotated to functional networks using a knowledge-based database, Ingenuity Pathway Analysis. In rats pretreated with vehicle, plantar incision caused robust hyperalgesia, up-regulated 36 genes and downregulated 90 genes in dorsal root ganglias one day after plantar incision. Capsaicin pretreatment attenuated pain behaviors, caused localized denervation of the dermis and epidermis, and prevented the incision-induced changes in 99 of 126 genes. The pathway analyses showed altered gene networks related to increased pro-inflammatory and decreased anti-inflammatory responses in dorsal root ganglias. Insulin-like growth factor signaling was identified as one of the major gene networks involved in the development of incisional pain. Expression of insulin-like growth factor -2 and IGFBP6 in dorsal root ganglia were independently validated with quantitative real-time polymerase chain reaction. We discovered a distinct subset of dorsal root ganglia genes and three key signaling pathways that are altered 24 h after plantar incision but are unchanged when incision was made after capsaicin infiltration in the skin. Further exploration of molecular mechanisms of incisional pain may yield novel therapeutic targets.
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Affiliation(s)
- Phu V Tran
- Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Malcolm E Johns
- Department of Anesthesiology, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Brian McAdams
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - Juan E Abrahante
- Informatics Institute, University of Minnesota, Minneapolis, MN, USA
| | - Donald A Simone
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - Ratan K Banik
- Department of Anesthesiology, School of Medicine, University of Minnesota, Minneapolis, MN, USA
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47
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Wang C, Hao H, He K, An Y, Pu Z, Gamper N, Zhang H, Du X. Neuropathic Injury-Induced Plasticity of GABAergic System in Peripheral Sensory Ganglia. Front Pharmacol 2021; 12:702218. [PMID: 34385921 PMCID: PMC8354334 DOI: 10.3389/fphar.2021.702218] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/25/2021] [Indexed: 12/30/2022] Open
Abstract
GABA is a major inhibitory neurotransmitter in the mammalian central nervous system (CNS). Inhibitory GABAA channel circuits in the dorsal spinal cord are the gatekeepers of the nociceptive input from the periphery to the CNS. Weakening of these spinal inhibitory mechanisms is a hallmark of chronic pain. Yet, recent studies have suggested the existence of an earlier GABAergic “gate” within the peripheral sensory ganglia. In this study, we performed systematic investigation of plastic changes of the GABA-related proteins in the dorsal root ganglion (DRG) in the process of neuropathic pain development. We found that chronic constriction injury (CCI) induced general downregulation of most GABAA channel subunits and the GABA-producing enzyme, glutamate decarboxylase, consistent with the weakening of the GABAergic inhibition at the periphery. Strikingly, the α5 GABAA subunit was consistently upregulated. Knock-down of the α5 subunit in vivo moderately alleviated neuropathic hyperalgesia. Our findings suggest that while the development of neuropathic pain is generally accompanied by weakening of the peripheral GABAergic system, the α5 GABAA subunit may have a unique pro-algesic role and, hence, might represent a new therapeutic target.
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Affiliation(s)
- Caixue Wang
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
| | - Han Hao
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
| | - Kaitong He
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
| | - Yating An
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
| | - Zeyao Pu
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
| | - Nikita Gamper
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China.,Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Hailin Zhang
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
| | - Xiaona Du
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
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Wilson H, Moore Z, Avsar P, Moda Vitoriano Budri A, O'Connor T, Nugent L, Patton D. Exploring the Role of Pain as an Early Indicator for Individuals at Risk of Pressure Ulcer Development: A Systematic Review. Worldviews Evid Based Nurs 2021; 18:299-307. [PMID: 34302432 DOI: 10.1111/wvn.12528] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2020] [Indexed: 01/29/2023]
Abstract
BACKGROUND Pressure ulcer (PU) development begins with an inflammatory response, arising due to pressure and shear forces causing changes to the cytoskeletal structure of cells. Thus, pain, synonymous with inflammation, may be an indicator of PU development. AIM To explore the role of pain as an indicator of PU development and to determine how this pain was measured. METHOD We searched PUBMED, CINAHL, SCOPUS, Cochrane, and EMBASE databases. A total of 879 records were returned, with eight satisfying the inclusion criteria. Narrative data synthesis was undertaken. The quality of studies was assessed using the evidence-based librarianship (EBL) checklist. RESULTS The studies were conducted between 2000 and 2019, and 75% (n = 6) employed a cross-sectional design. The mean sample size was 760 participants (SD = 703). Of the included studies, 87.5% (n = 7) identified that pain was associated with PU development. The most frequent pain assessment tool was the numeric rating scale (37.5%; n = 3). Using the EBL checklist, 62.5% (n = 5) of the studies scored ≥75%, reflecting validity. LINKING EVIDENCE TO ACTION Pain is associated with PU development; however, further research is required to validate these findings and assess the characteristics associated with pain as a symptom preceding PU development.
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Affiliation(s)
- Hannah Wilson
- School of Nursing and Midwifery, Skin, Wounds and Trauma Research Centre (SWaT), Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland.,Cardiovascular Research Institute Dublin, Mater Private Network, Dublin, Ireland
| | - Zena Moore
- School of Nursing and Midwifery, Skin, Wounds and Trauma Research Centre (SWaT), Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland.,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Vic, Australia.,Department of Public Health, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.,Lida Institute, Shanghai, China.,University of Wales, Cardiff, UK.,Fakeeh College of Health Sciences, Jeddah, Saudi Arabia
| | - Pinar Avsar
- School of Nursing and Midwifery, Skin, Wounds and Trauma Research Centre (SWaT), Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland
| | - Aglecia Moda Vitoriano Budri
- School of Nursing and Midwifery, Skin, Wounds and Trauma Research Centre (SWaT), Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland
| | - Tom O'Connor
- School of Nursing and Midwifery, Skin, Wounds and Trauma Research Centre (SWaT), Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland.,Lida Institute, Shanghai, China.,Fakeeh College of Health Sciences, Jeddah, Saudi Arabia
| | - Linda Nugent
- School of Nursing and Midwifery, Skin, Wounds and Trauma Research Centre (SWaT), Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland.,Fakeeh College of Health Sciences, Jeddah, Saudi Arabia
| | - Declan Patton
- School of Nursing and Midwifery, Skin, Wounds and Trauma Research Centre (SWaT), Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland.,Fakeeh College of Health Sciences, Jeddah, Saudi Arabia.,Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia
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49
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D'Arcy Y, Mantyh P, Yaksh T, Donevan S, Hall J, Sadrarhami M, Viktrup L. Treating osteoarthritis pain: mechanisms of action of acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, and nerve growth factor antibodies. Postgrad Med 2021; 133:879-894. [PMID: 34252357 DOI: 10.1080/00325481.2021.1949199] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Osteoarthritis (OA) is a common difficult-to-treat condition where the goal, in the absence of disease-modifying treatments, is to alleviate symptoms such as pain and loss of function. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids are common pharmacologic treatments for OA. Antibodies directed against nerve growth factor (NGF-Abs) are a new class of agents under clinical investigation for the treatment of OA. This narrative review describes (and uses schematics to visualize) nociceptive signaling, chronification of pain, and the mechanisms of action (MOAs) of these different analgesics in the context of OA-related pain pathophysiology. Further, the varying levels of efficacy and safety of these agents observed in patients with OA is examined, based on an overview of published clinical data and/or treatment guidelines (when available), in the context of differences in their MOAs.
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Affiliation(s)
- Yvonne D'Arcy
- Independent Nurse Practitioner, Ponte Vedra Beach, FL, USA
| | - Patrick Mantyh
- Department of Pharmacology and Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Tony Yaksh
- Department of Anesthesiology and Pharmacology, University of California at San Diego, San Diego, CA, USA
| | | | - Jerry Hall
- Lilly Biomedicines, US/Global Medical Affairs, Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Lars Viktrup
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
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50
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Kimura LF, Novaes LS, Picolo G, Munhoz CD, Cheung CW, Camarini R. How environmental enrichment balances out neuroinflammation in chronic pain and comorbid depression and anxiety disorders. Br J Pharmacol 2021; 179:1640-1660. [PMID: 34076891 DOI: 10.1111/bph.15584] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 04/05/2021] [Accepted: 05/17/2021] [Indexed: 11/30/2022] Open
Abstract
Depression and anxiety commonly occur in chronic pain states and the coexistence of these diseases worsens outcomes for both disorders and may reduce treatment adherence and response. Despite the advances in the knowledge of chronic pain mechanisms, pharmacological treatment is still unsatisfactory. Research based on exposure to environmental enrichment is currently under investigation and seems to offer a promising low-cost strategy with no side effects. In this review, we discuss the role of inflammation as a major biological substrate and aetiological factor of chronic pain and depression/anxiety and report a collection of preclinical evidence of the effects and mechanisms of environmental enrichment. As microglia participates in the development of both conditions, we also discuss microglia as a potential target underlying the beneficial actions of environmental enrichment in chronic pain and comorbid depression/anxiety. We also discuss how alternative interventions under clinical guidelines, such as environmental enrichment, may improve treatment compliance and patient outcomes.
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Affiliation(s)
- Louise F Kimura
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, Brazil
| | - Leonardo S Novaes
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Gisele Picolo
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, Brazil
| | - Carolina D Munhoz
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Chi W Cheung
- Department of Anesthesiology, University of Hong Kong, Hong Kong
| | - Rosana Camarini
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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