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Cronin SJF, Rao S, Tejada MA, Turnes BL, Licht-Mayer S, Omura T, Brenneis C, Jacobs E, Barrett L, Latremoliere A, Andrews N, Channon KM, Latini A, Arvanites AC, Davidow LS, Costigan M, Rubin LL, Penninger JM, Woolf CJ. Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer. Sci Transl Med 2022; 14:eabj1531. [PMID: 36044597 PMCID: PMC9985140 DOI: 10.1126/scitranslmed.abj1531] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.
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Affiliation(s)
- Shane J. F. Cronin
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
- Institute of Molecular Biotechnology Austria (IMBA), Dr. Bohrgasse 3, Vienna A-1030, Austria
| | - Shuan Rao
- Institute of Molecular Biotechnology Austria (IMBA), Dr. Bohrgasse 3, Vienna A-1030, Austria
| | - Miguel A. Tejada
- Institute of Molecular Biotechnology Austria (IMBA), Dr. Bohrgasse 3, Vienna A-1030, Austria
| | - Bruna Lenfers Turnes
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Simon Licht-Mayer
- Institute of Molecular Biotechnology Austria (IMBA), Dr. Bohrgasse 3, Vienna A-1030, Austria
| | - Takao Omura
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Christian Brenneis
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Emily Jacobs
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Lee Barrett
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Alban Latremoliere
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
- Departments of Neurosurgery and Neuroscience, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Nick Andrews
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Keith M. Channon
- Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Alexandra Latini
- LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil
| | - Anthony C. Arvanites
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Lance S. Davidow
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Michael Costigan
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Lee L. Rubin
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Josef M. Penninger
- Institute of Molecular Biotechnology Austria (IMBA), Dr. Bohrgasse 3, Vienna A-1030, Austria
- Department of Medical Genetics, Life Sciences Institute, UBC, Vancouver, BC V6T 1Z3, Canada
| | - Clifford J. Woolf
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
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Yeo JH, Roh DH. Dexmedetomidine Co-Administered with Lidocaine Decreases Nociceptive Responses and Trigeminal Fos Expression without Motor Dysfunction and Hypotension in a Murine Orofacial Formalin Model. Life (Basel) 2022; 12:life12020215. [PMID: 35207502 PMCID: PMC8878816 DOI: 10.3390/life12020215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 11/16/2022] Open
Abstract
Administration of dexmedetomidine significantly induces sedation and anti-nociception in several nociceptive models, but clinical trials are restricted due to adverse side effects, including lethargy, hypotension, and bradycardia. Herein, we investigated whether intraperitoneal inoculation of dexmedetomidine reduced the orofacial nociceptive response and affected motor coordination and blood pressure and examined whether a lower dose of dexmedetomidine in combination with 0.5% lidocaine produced an antinociceptive effect without any adverse side events in a murine model. To perform the experiment, 5% formalin (10 µL) was subcutaneously inoculated into the right upper lip, and the rubbing responses were counted for 45 min. Different doses of dexmedetomidine combined with 0.5% lidocaine were administered 10 and 30 min before formalin injection, respectively. Dexmedetomidine (10 μg/kg) significantly reduced orofacial nociceptive responses during the second phase of the formalin test and decreased the expression of Fos in trigeminal nucleus caudalis (TNC). Besides, a high dose of dexmedetomidine (30 μg/kg) induced lessening physical ability and significantly reduced systolic pressure and heart rate. When 0.5% lidocaine was injected subcutaneously, nociceptive responses were reduced only in the first phase. Interestingly, although a low dose of dexmedetomidine (3 μg/kg) alone did not show an antinociceptive effect, its co-administration with lidocaine significantly reduced the nociceptive response in both phases and decreased TNC Fos expression without motor dysfunction and hypotension. This finding suggests that the combination of a low-dose of systemic dexmedetomidine with lidocaine may be a safe medicinal approach for acute inflammatory pain management in the orofacial region, particularly mucogingival pain.
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Mirasheh MH, Zohrehvand MR, Kazemi R, Bahari Z, Bahrami F, Jangravi Z, Graily M. The Analgesic and Anxiolytic Activity of Resveratrol Mediated by Different Sub-Types of α-Adrenoceptors of Anterior Cingulate Cortex Following Neuropathic Pain in Male Rats. ACTA ACUST UNITED AC 2020. [DOI: 10.30699/jambs.28.129.183] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Bembrick AL, Boorman DC, Keay KA. Disability-specific genes GRIN1, GRIN2 and CNR1 show injury-dependent protein expression in the lumbar spinal cord of CCI rats. Neurosci Lett 2020; 728:134982. [PMID: 32320718 DOI: 10.1016/j.neulet.2020.134982] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 04/06/2020] [Accepted: 04/10/2020] [Indexed: 11/28/2022]
Abstract
The sensory changes triggered by peripheral nerve injury result from functional changes in both neurons and glia in the dorsal horn of the spinal cord. Whether the disrupted affective-motivational states often comorbid with injury-evoked changes in sensation are driven directly by these functional changes is a question only recently investigated. Using a combination of GeneChip microarrays and RT-PCR techniques we identified differences in mRNA expression unique to rats with sustained changes to their social behaviour following sciatic nerve chronic constriction injury (CCI). Amongst these changes were the mRNAs encoding several of the NMDA subunits and the CB1 receptor. However, as protein translation is not a necessary consequence of the upregulation or downregulation of genes we decided to evaluate the functional significance of our initial observations using immunohistochemical detection of their translated protein products to determine their location and abundance in the lumbar spinal cord. Spinal cord tissue from rats with ('Affected'), and without ('Unaffected') changes in social behaviour after CCI was compared with tissue from uninjured controls. The expression of NMDA-1 (NR1) subunit, NMDA-2D subunit, Cannabinoid Receptor 1 (CB1), Glucocorticoid Receptor (GR) and Glial Fibrillary Acidic Protein (GFAP) immunoreactivities was quantified for these rats and revealed that nerve injury increased the expression of NMDA-2D, CB1 and GFAP immunoreactivity compared to uninjured controls. However, these changes were not specific to rats whose social behaviours were 'Affected' or 'Unaffected' by the nerve injury. Our data thus suggest that the development and expression of changes in social behaviour seen in a proportion of rats following CCI are unlikely to be directly related to the spinal changes in NMDA-2D, CB1 and GFAP expression induced by the nerve injury.
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Affiliation(s)
- Alison L Bembrick
- School of Medical Sciences, Discipline of Anatomy & Histology, Faculty of Medicine and Health, University of Sydney, NSW, 2006, Australia
| | - Damien C Boorman
- School of Medical Sciences, Discipline of Anatomy & Histology, Faculty of Medicine and Health, University of Sydney, NSW, 2006, Australia
| | - Kevin A Keay
- School of Medical Sciences, Discipline of Anatomy & Histology, Faculty of Medicine and Health, University of Sydney, NSW, 2006, Australia.
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Chia JSM, Izham NAM, Farouk AAO, Sulaiman MR, Mustafa S, Hutchinson MR, Perimal EK. Zerumbone Modulates α 2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models. Front Pharmacol 2020; 11:92. [PMID: 32194397 PMCID: PMC7064019 DOI: 10.3389/fphar.2020.00092] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 01/27/2020] [Indexed: 01/08/2023] Open
Abstract
Zerumbone has shown great potential in various pathophysiological models of diseases, particularly in neuropathic pain conditions. Further understanding the mechanisms of action is important to develop zerumbone as a potential anti-nociceptive agent. Numerous receptors and pathways function to inhibit and modulate transmission of pain signals. Previously, we demonstrated involvement of the serotonergic system in zerumbone's anti-neuropathic effects. The present study was conducted to determine zerumbone's modulatory potential involving noradrenergic, transient receptor potential vanilloid type 1 (TRPV1) and N-methyl-D-aspartate (NMDA) receptors in chronic constriction injury (CCI)-induced in vitro and lipopolysaccharide (LPS)-induced SH-SY5Y in vitro neuroinflammatory models. von Frey filament and Hargreaves plantar tests were used to assess allodynia and hyperalgesia in the chronic constriction injury-induced neuropathic pain mouse model. Involvement of specific adrenoceptors were investigated using antagonists- prazosin (α1-adrenoceptor antagonist), idazoxan (α2-adrenoceptor antagonist), metoprolol (β1-adrenoceptor antagonist), ICI 118,551 (β2-adrenoceptor antagonist), and SR 59230 A (β3-adrenoceptor antagonist), co-administered with zerumbone (10 mg/kg). Involvement of excitatory receptors; TRPV and NMDA were conducted using antagonists capsazepine (TRPV1 antagonist) and memantine (NMDA antagonist). Western blot was conducted to investigate the effect of zerumbone on the expression of α2A-adrenoceptor, TRPV1 and NMDA NR2B receptors in CCI-induced whole brain samples of mice as well as in LPS-induced SH-SY5Y neuroblastoma cells. Pre-treatment with α1- and α2-adrenoceptor antagonists significantly attenuated both anti-allodynic and anti-hyperalgesic effects of zerumbone. For β-adrenoceptors, only β2-adrenoceptor antagonist significantly reversed the anti-allodynic and anti-hyperalgesic effects of zerumbone. β1-adrenoceptor antagonist only reversed the anti-allodynic effect of zerumbone. The anti-allodynic and anti-hyperalgesic effects of zerumbone were both absent when TRPV1 and NMDA receptors were antagonized in both nociceptive assays. Zerumbone treatment markedly decreased the expression of α2A-adrenoceptor, while an up-regulation was observed of NMDA NR2B receptors. Expression of TRPV1 receptors however did not significantly change. The in vitro study, representing a peripheral model, demonstrated the reduction of both NMDA NR2B and TRPV1 receptors while significantly increasing α2A-adrenoceptor expression in contrast to the brain samples. Our current findings suggest that the α1-, α2-, β1- and β2-adrenoceptors, TRPV1 and NMDA NR2B are essential for the anti-allodynic and antihyperalgesic effects of zerumbone. Alternatively, we demonstrated the plasticity of these receptors through their response to zerumbone's administration.
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Affiliation(s)
- Jasmine Siew Min Chia
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.,Centre for Community Health Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Noor Aishah Mohammed Izham
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Ahmad Akira Omar Farouk
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Mohd Roslan Sulaiman
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Sanam Mustafa
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Mark R Hutchinson
- Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, SA, Australia
| | - Enoch Kumar Perimal
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.,Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, SA, Australia
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Bahari Z, Meftahi GH. Spinal α 2 -adrenoceptors and neuropathic pain modulation; therapeutic target. Br J Pharmacol 2019; 176:2366-2381. [PMID: 30657594 DOI: 10.1111/bph.14580] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/23/2018] [Accepted: 12/04/2018] [Indexed: 12/22/2022] Open
Abstract
Neuropathic pain can arise from disease or damage to the nervous system. The most common symptoms of neuropathic pain include spontaneous pain, allodynia, and hyperalgesia. There is still limited knowledge about the factors that initiate and maintain neuropathic pain. However, ample evidence has proved the antinociceptive role of spinal α-adrenoceptors following nerve injury. It is well-documented that noradrenergic descending pathways from supraspinal loci exert an inhibitory influence on the spinal cord nociceptive neurons, mostly through the activation of spinal α2 -adrenoceptors. This, in turn, suppresses transmission of pain input and the hyperexcitability of spinal dorsal horn neurons. There is considerable evidence demonstrating that spinal application of α2 -adrenoceptor agonists leads to analgesic effects in animal models of neuropathic pain. Today, despite the recent rapid development of neuroscience and drug discovery, effective drugs with clear basic mechanisms have remained a mystery. Here, we give an overview of the cellular mechanisms through which brainstem adrenergic descending inhibitory processing can alter spinal pain transmission to the higher centres, and how these pathways change in neuropathic pain conditions focusing on the role of spinal α2 -adrenoceptors in the spinal dorsal horn. We then suggest that α2 -adrenoceptor agonist may be useful to treat neuropathic pain. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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Affiliation(s)
- Zahra Bahari
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Department of Physiology and Medical Physics, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Zupcic SG, Zupcic M, Duzel V, Šimurina T, Milošević M, Basic S, Vuletic V, Kapural L. Effect of clonidine on the cutaneous silent period during spinal anesthesia. World J Clin Cases 2018; 6:1136-1145. [PMID: 30613672 PMCID: PMC6306629 DOI: 10.12998/wjcc.v6.i16.1136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/17/2018] [Accepted: 11/07/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the effect of clonidine on the cutaneous silent period (CSP) during spinal anesthesia. METHODS A total of 67 adult patients were included in this randomized, prospective, single-center, double-blind trial. They did not have neurological disorders and were scheduled for inguinal hernia repair surgery. This trial was registered on ClinicalTrials.gov (NTC03121261). The patients were randomized into two groups with regards to the intrathecally administered solution: (1) 15 mg of 0.5% levobupivacaine with 50 µg of 0.015% clonidine, or (2) 15 mg of 0.5% levobupivacaine alone. There were 34 patients in the levobupivacaine-clonidine (LC) group and 33 patients in the levobupivacaine (L) group. CSP and its latency were measured four times: prior to the subarachnoid block (SAB), after motor block regression to the 0 level of the Bromage scale, with ongoing sensory blockade, and both 6 and 24 h after SAB. RESULTS Only data from 30 patients in each group were analyzed. There were no significant differences between the groups investigated preoperatively and after 24 h. The CSP of the L group at the time point when the Bromage scale was 0 was 44.8 ± 8.1 ms, while in the LC group it measured 40.2 ± 3.8 ms (P = 0.007). The latency in the L group at the time point when the Bromage scale was 0 was 130.3 ± 10.2 ms, and in the LC group it was 144.7 ± 8.3 ms (P < 0.001). The CSP of the L group after 6 h was 59.6 ± 9.8 ms, while in the LC group it was 44.5 ± 5.0 ms (P < 0.001). The latency in the L group after 6 h was 110.4 ± 10.6 ms, while in LC group it was 132.3 ± 9.7 ms (P < 0.001). CONCLUSION Intrathecal addition of clonidine to levobupivacaine for SAB in comparison with levobupivacaine alone results in a diminished inhibitory tonus and shortened CSP.
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Affiliation(s)
- Sandra Graf Zupcic
- Clinic of Neurology, Clinical Hospital Centre Rijeka, Rijeka 51000, Croatia
| | - Miroslav Zupcic
- Faculty of Medicine, J. J. Strossmayer University, Osijek 31000, Croatia
- Clinic of Anesthesiology and Intensive Care Medicine, Clinical Hospital Centre Rijeka, Rijeka 51000, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia
| | - Viktor Duzel
- Department of Anaesthesia, Barking, Havering and Redbridge University Hospitals NHS Trust, London RM7 0AG, United Kingdom
| | - Tatjana Šimurina
- Faculty of Medicine, J. J. Strossmayer University, Osijek 31000, Croatia
- Department of Health Studies University of Zadar, Zadar 23000, Croatia
- Department of Anesthesiology and Intensive Care Medicine, General Hospital Zadar, Zadar 23000, Croatia
| | - Milan Milošević
- University of Zagreb, School of Medicine, Andrija Stampar School of Public Health WHO Collaborative Centre for Occupational Health, Zagreb 10000, Croatia
| | - Silvio Basic
- Faculty of Medicine, J. J. Strossmayer University, Osijek 31000, Croatia
- Department of Neurology, Clinical Hospital Dubrava, Zagreb 10000, Croatia
| | - Vladimira Vuletic
- Clinic of Neurology, Clinical Hospital Centre Rijeka, Rijeka 51000, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia
| | - Leonardo Kapural
- Center for Clinical Research, Winston Salem, NC 27103, United States
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Tseng TJ, Yang ML, Hsieh YL, Ko MH, Hsieh ST. Nerve Decompression Improves Spinal Synaptic Plasticity of Opioid Receptors for Pain Relief. Neurotox Res 2017; 33:362-376. [PMID: 28836121 DOI: 10.1007/s12640-017-9799-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 07/24/2017] [Accepted: 08/10/2017] [Indexed: 01/05/2023]
Abstract
Nerve decompression is an essential therapeutic strategy for pain relief clinically; however, its potential mechanism remains poorly understood. Opioid analgesics acting on opioid receptors (OR) within the various regions of the nervous system have been used widely for pain management. We therefore hypothesized that nerve decompression in a neuropathic pain model of chronic constriction injury (CCI) improves the synaptic OR plasticity in the dorsal horn, which is in response to alleviate pain hypersensitivity. After CCI, the Sprague-Dawley rats were assigned into Decompression group, in which the ligatures around the sciatic nerve were removed at post-operative week 4 (POW 4), and a CCI group, in which the ligatures remained. Pain hypersensitivity, including thermal hyperalgesia and mechanical allodynia, was entirely normalized in Decompression group within the following 4 weeks. Substantial reversal of mu- and delta-OR immunoreactive (IR) expressions in Decompression group was detected in primary afferent terminals in the dorsal horn. In Decompression group, mu-OR antagonist (CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 [Disulfide Bridge: 2-7]) and delta-OR antagonist (NTI, 17-(cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan hydrochloride) re-induced pain hypersensitivity by intrathecal administration in a dose-responsive manner. Additionally, mu-OR agonist (DAMGO, [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin) and delta-OR agonist (SNC80, ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethyl-benzamide) were administrated intrathecally to attenuating CCI-induced chronic and acute pain hypersensitivity dose-dependently. Our current results strongly suggested that nerve decompression provides the opportunity for improving the synaptic OR plasticity in the dorsal horn and pharmacological blockade presents a novel insight into the therapeutic strategy for pain hypersensitivity.
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Affiliation(s)
- To-Jung Tseng
- Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan.,Department of Medical Education, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan
| | - Ming-Ling Yang
- Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan.,Department of Medical Education, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan
| | - Yu-Lin Hsieh
- Department of Anatomy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Miau-Hwa Ko
- Department of Anatomy, China Medical University, Taichung, 40402, Taiwan
| | - Sung-Tsang Hsieh
- Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Sec 1, Taipei, 10051, Taiwan. .,Department of Neurology, National Taiwan University Hospital, Taipei, 10002, Taiwan.
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Moore DM, McCrory C. The Proteomics of Intrathecal Analgesic agents for Chronic Pain. Curr Neuropharmacol 2017; 15:198-205. [PMID: 26907496 PMCID: PMC5412698 DOI: 10.2174/1570159x14666160224124446] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 08/21/2015] [Accepted: 08/28/2015] [Indexed: 12/19/2022] Open
Abstract
Chronic pain remains a challenging clinical problem with a growing socio-economic burden for the state. Its prevalence is high and many of the patients are of work age. Our knowledge regarding the pathophysiology of chronic pain is poor. The consensus view is that the central nervous system plays a key role in the persistence of pain after an initiating event has long ceased. However the specifics of this biological response to an initiating event remains unclear. There is a growing body of evidence to support the concept that a central neuroimmune response is initiated and a number of small peptides have been implicated in this process following cerebrospinal fluid analysis in patients with chronic pain. This central biosynthetic peptide response leads to a process called central sensitization. Therapy is aimed at modulating and even inhibiting this response. However current pharmacological therapeutic options are limited in efficacy with significant deleterious side effect profiles. Proteomic studies extend single molecule analysis by identifying the components of biological networks and pathways and defining their interactions. This tool offers the potential to provide a molecular overview of the biological processes involved in chronic pain. It will also facilitate examination of gene-drug interactions. This technique offers a mechanism of defining the central biological responses that result in chronic pain and this information may facilitate the development of better therapies.
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Rao KG, Shukla A, Misra S. Postoperative Analgesia After Panhysterectomy, Addition of Clonidine to Bupivacaine: Boon for the Patients. Anesth Essays Res 2017; 11:340-344. [PMID: 28663618 PMCID: PMC5490093 DOI: 10.4103/0259-1162.186610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Postoperative period after panhysterectomy is very painful as there is too much tissue handling. In the practice of regional anesthesia neuraxial, opioids have been used extensively as an adjuvant to bupivacaine to enhance the potency and duration of sensory and motor block produced by bupivacaine with satisfactory results. However, delayed respiratory depression by opioids has prompted further research to develop nonopioid analgesics. This study was undertaken to assess the degree of sensory and motor block and postoperative analgesia provided by low dose 50 μg intrathecal clonidine admixed with 0.5% hyperbaric bupivacaine as compared to bupivacaine alone in patients undergoing a total abdominal hysterectomy. MATERIALS AND METHODS Hundred adult patients of American Society of Anesthesiologist Class 1 and 2 were randomly allocated to Group A and Group B. Group A patients received 15 mg 0.5% hyperbaric bupivacaine with 50 μg clonidine intrathecally. Group B patients received 15 mg 0.5% hyperbaric bupivacaine with normal saline. OBSERVATION AND RESULTS The mean duration of motor block was significantly higher in Group A (270.80± 66.0 min) as compared to Group B (184.60 ± 72.03 min), with statistically significant difference. There was also statistically significant difference in the duration of sensory block between Group A (290.20 ± 80.27 min) and Group B (190.83 ± 86.90 min). The duration of postoperative analgesia was significantly higher in Group A as compared to Group B (541.06 ± 130.64 min and 252.80 ± 84.10 min respectively). CONCLUSION Addition of intrathecal clonidine 50 μg to bupivacaine (15 mg, 0.5%) prolongs the duration of sensory and motor block and duration of analgesia, thus produces an effective spinal anesthesia and good postoperative analgesia for longer duration and reduced postoperative analgesic requirement.
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Affiliation(s)
- Keshav Govind Rao
- Department of Anesthesiology, Integral Institute of Medical Sciences and Research, Lucknow, Uttar Pradesh, India
| | - Aparna Shukla
- Department of Anesthesiology, Integral Institute of Medical Sciences and Research, Lucknow, Uttar Pradesh, India
| | - Shilpi Misra
- Department of Anesthesiology, Integral Institute of Medical Sciences and Research, Lucknow, Uttar Pradesh, India
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11
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Makau CM, Towett PK, Abelson KSP, Kanui TI. Modulation of formalin-induced pain-related behaviour by clonidine and yohimbine in the Speke's hinged tortoise (Kiniskys spekii). J Vet Pharmacol Ther 2016; 40:439-446. [PMID: 27891620 DOI: 10.1111/jvp.12374] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 09/19/2016] [Indexed: 01/12/2023]
Abstract
The study was designed to investigate the involvement of noradrenergic and serotonergic receptor systems in the modulation of formalin-induced pain-related behaviour in the Speke's hinged tortoise. Intradermal injection of 100 μL of formalin at a dilution of 12.5% caused pain-related behaviour (hindlimb withdrawal) that lasted for a mean time of 19.28 min (monophasic response). Intrathecal administration of clonidine (α2 -adrenergic receptor agonist) and yohimbine (α2 -adrenergic receptor antagonist) at a dose of 40 μg/kg and 37.5 μg/kg or 50 μg/kg, respectively, caused a highly significant reduction in the duration of the formalin-induced pain-related behaviour. The effect of clonidine was reversed by intrathecal administration of yohimbine at a dose of 26.7 μg/kg. The effect of yohimbine at a dose of 50 μg/kg was reversed by intrathecal injection of 20 μg/kg of the serotonergic receptor antagonist methysergide maleate. When performing antagonistic reactions, the administration of the antagonist was followed immediately by that of the agonist. The study indicates that for experimental purposes, intrathecal route of drug administration through the atlanto-occipital joint is effective in tortoises. The data also suggest that testudines have noradrenergic and serotonergic systems that appear to play a role in the modulation of pain in this species.
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Affiliation(s)
- C M Makau
- School of Pure and Applied Sciences, Mount Kenya University, Nakuru, Kenya
| | - P K Towett
- Department of Veterinary Anatomy and Physiology, University of Nairobi, Nairobi, Kenya
| | - K S P Abelson
- Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - T I Kanui
- School of Agriculture and Veterinary Sciences, South Eastern Kenya University, Kitui, Kenya
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12
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Bravo L, Mico JA, Rey-Brea R, Camarena-Delgado C, Berrocoso E. Effect of DSP4 and desipramine in the sensorial and affective component of neuropathic pain in rats. Prog Neuropsychopharmacol Biol Psychiatry 2016; 70:57-67. [PMID: 27181607 DOI: 10.1016/j.pnpbp.2016.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 05/08/2016] [Accepted: 05/09/2016] [Indexed: 12/13/2022]
Abstract
Previous findings suggest that neuropathic pain induces characteristic changes in the noradrenergic system that may modify the sensorial and affective dimensions of pain. We raise the hypothesis that different drugs that manipulate the noradrenergic system can modify specific domains of pain. In the chronic constriction injury (CCI) model of neuropathic pain, the sensorial (von Frey and acetone tests) and the affective (place escape/avoidance paradigm) domains of pain were evaluated in rats 1 and 2weeks after administering the noradrenergic neurotoxin [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] (DSP4, 50mg/kg). In other animals, we evaluated the effect of enhancing noradrenergic tone in the 2weeks after injury by administering the antidepressant desipramine (10mg/kg/day, delivered by osmotic minipumps) during this period, a noradrenaline reuptake inhibitor. Moreover, the phosphorylation of the extracellular signal regulated kinases (p-ERK) in the anterior cingulate cortex (ACC) was also assessed. The ACC receives direct inputs from the main noradrenergic nucleus, the locus coeruleus, and ERK activation has been related with the expression of pain-related negative affect. These studies revealed that DSP4 almost depleted noradrenergic axons in the ACC and halved noradrenergic neurons in the locus coeruleus along with a decrease in the affective dimension and an increased of p-ERK in the ACC. However, it did not modify sensorial pain perception. By contrast, desipramine reduced pain hypersensitivity, while completely impeding the reduction of the affective pain dimension and without modifying the amount of p-ERK. Together results suggest that the noradrenergic system may regulate the sensorial and affective sphere of neuropathic pain independently.
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Affiliation(s)
- Lidia Bravo
- Neuropsychopharmacology & Psychobiology Research Group, University of Cádiz, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28007 Madrid, Spain; Psychobiology Area, Department of Psychology, University of Cadiz, Spain
| | - Juan A Mico
- Neuropsychopharmacology & Psychobiology Research Group, University of Cádiz, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28007 Madrid, Spain; Department of Neuroscience, University of Cádiz, Spain
| | - Raquel Rey-Brea
- Neuropsychopharmacology & Psychobiology Research Group, University of Cádiz, Spain
| | | | - Esther Berrocoso
- Neuropsychopharmacology & Psychobiology Research Group, University of Cádiz, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28007 Madrid, Spain; Psychobiology Area, Department of Psychology, University of Cadiz, Spain.
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13
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Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease. Neural Plast 2016; 2016:6383240. [PMID: 27747105 PMCID: PMC5056271 DOI: 10.1155/2016/6383240] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 08/29/2016] [Indexed: 12/27/2022] Open
Abstract
In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain.
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Yeo JH, Yoon SY, Kim SJ, Oh SB, Lee JH, Beitz AJ, Roh DH. Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension. Int J Cancer 2016; 138:2466-76. [PMID: 26704560 DOI: 10.1002/ijc.29980] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 11/26/2015] [Accepted: 12/14/2015] [Indexed: 01/18/2023]
Abstract
Cancer chemotherapy with platinum-based antineoplastic agents including oxaliplatin frequently results in a debilitating and painful peripheral neuropathy. We evaluated the antinociceptive effects of the alpha-2 adrenoceptor agonist, clonidine on oxaliplatin-induced neuropathic pain. Specifically, we determined if (i) the intraperitoneal (i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin-induced neuropathy and (ii) concurrent inhibition of p38 mitogen-activated protein kinase (MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's antiallodynic effect. Clonidine (0.01-0.1 mg kg(-1), i.p.), with or without SB203580(1-10 nmol, intrathecal) was administered two weeks after oxaliplatin injection(10 mg kg(-1), i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Postmortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p-p38 and p-ERK) were quantified 30 min or 4 hr after drug injection in the spinal cord dorsal horn of treated and control mice. Clonidine dose-dependently reduced oxaliplatin-induced mechanical allodynia and spinal p-p38 MAPK expression, but not p-ERK. At 0.1 mg kg(-1), clonidine also impaired motor coordination and decreased blood pressure. A 10 nmol dose of SB203580 alone significantly reduced mechanical allodynia and p-p38 MAPK expression, while a subeffective dose(3 nmol) potentiated the antiallodynic effect of 0.03 mg kg(-1) clonidine and reduced the increased p-p38 MAPK. Coadministration of SB203580 and 0.03 mg kg(-1) clonidine decreased allodynia similar to that of 0.10 mg kg(-1) clonidine, but without significant motor or vascular effects. These findings demonstrate that clonidine treatment reduces oxaliplatin-induced mechanical allodynia. The concurrent administration of SB203580 reduces the dosage requirements for clonidine, thereby alleviating allodynia without producing undesirable motor or cardiovascular effects.
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Affiliation(s)
- Ji-Hee Yeo
- Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
| | - Seo-Yeon Yoon
- Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.,Department of Neurobiology and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Sol-Ji Kim
- Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
| | - Seog-Bae Oh
- Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.,Department of Neurobiology and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Jang-Hern Lee
- Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Alvin J Beitz
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN
| | - Dae-Hyun Roh
- Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
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15
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Singh RB, Chopra N, Choubey S, Tripathi RK, Prabhakar, Mishra A. Role of Clonidine as adjuvant to intrathecal bupivacaine in patients undergoing lower abdominal surgery: A randomized control study. Anesth Essays Res 2015; 8:307-12. [PMID: 25886326 PMCID: PMC4258982 DOI: 10.4103/0259-1162.143119] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background: Neuraxial anesthesia greatly expands the anesthesiologist armamentarium, providing alternatives to general anesthesia, especially in the lower abdominal surgeries. Clonidine, an alpha-2 adrenergic agonist, has a variety of actions, including potentiation of effects of local anesthetics. This study was undertaken to assess the degree of sensory and motor block and postoperative analgesia provided by low dose (50 mcg) intrathecal clonidine admixed with bupivacaine. Aims: The aim of this study is to establish efficacy and safety of intrathecal clonidine as adjuvant to bupivacaine. Settings and Design: The type of the study was double-blind randomized trial. Materials and Methods: Hundred patients were randomly allocated in two groups, A and B. Group A received bupivacaine 0.5%, 3 ml with placebo (normal saline 0.33 ml) and Group B, bupivacaine 0.5%, 3 ml with clonidine 50 μg (0.33 ml). Statistical Analysis Used: Statistical Package for Social Sciences version 15.0 statistical analysis software. Results: Mean duration of motor block was significantly higher in Group B (280.80 ± 66.88 min) as compared with Group A (183.60 ± 77.06 min). Significant difference in duration of sensory block was noted between Group B (295.20 ± 81.17 min) and Group A (190.80 ± 86.94 min). Duration of postoperative analgesia was significantly higher in Group B as compared to Group A (551.06 ± 133.64 min and 254.80 ± 84.19 min respectively). Mean visual analog scale scores at different time intervals were significantly lower in the study group (except for 4-h time interval), but the control group had better hemodynamic stability as compared with study group. Conclusion: The findings in this study suggested that use of clonidine 50 μg added to bupivacaine for spinal anesthesia effectively increased the duration of sensory block, duration of motor block, and duration of analgesia.
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Affiliation(s)
- Raj Bahadur Singh
- Department of Anaesthesiology and Critical Care, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradersh, India
| | - Neetu Chopra
- Department of Anaesthesiology and Critical Care, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradersh, India
| | - Sanjay Choubey
- Department of Anaesthesiology and Critical Care, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradersh, India
| | - R K Tripathi
- Department of Anaesthesiology and Critical Care, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradersh, India
| | - Prabhakar
- Department of Anaesthesiology and Critical Care, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradersh, India
| | - Abhishek Mishra
- Department of Anaesthesiology and Critical Care, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradersh, India
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16
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Yoon SY, Kang SY, Kim HW, Kim HC, Roh DH. Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination. Biol Pharm Bull 2015; 38:1320-7. [PMID: 26328487 DOI: 10.1248/bpb.b15-00183] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced anti-nociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore- or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.
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Affiliation(s)
- Seo-Yeon Yoon
- Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University
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Lemmens S, Brône B, Dooley D, Hendrix S, Geurts N. Alpha-adrenoceptor modulation in central nervous system trauma: pain, spasms, and paralysis--an unlucky triad. Med Res Rev 2014; 35:653-77. [PMID: 25546087 DOI: 10.1002/med.21337] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Many researchers have attempted to pharmacologically modulate the adrenergic system to control locomotion, pain, and spasms after central nervous system (CNS) trauma, although such efforts have led to conflicting results. Despite this, multiple studies highlight that α-adrenoceptors (α-ARs) are promising therapeutic targets because in the CNS, they are involved in reactivity to stressors and regulation of locomotion, pain, and spasms. These functions can be activated by direct modulation of these receptors on neuronal networks in the brain and the spinal cord. In addition, these multifunctional receptors are also broadly expressed on immune cells. This suggests that they might play a key role in modulating immunological responses, which may be crucial in treating spinal cord injury and traumatic brain injury as both diseases are characterized by a strong inflammatory component. Reducing the proinflammatory response will create a more permissive environment for axon regeneration and may support neuromodulation in combination therapies. However, pharmacological interventions are hindered by adrenergic system complexity and the even more complicated anatomical and physiological changes in the CNS after trauma. This review is the first concise overview of the pros and cons of α-AR modulation in the context of CNS trauma.
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Affiliation(s)
- Stefanie Lemmens
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Bert Brône
- Department of Physiology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Dearbhaile Dooley
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Sven Hendrix
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Nathalie Geurts
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
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18
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Aira Z, Barrenetxea T, Buesa I, Azkue JJ. Plasticity of α2-adrenergic spinal antinociception following nerve injury: selective, bidirectional interaction with the delta opioid receptor. Brain Res 2014; 1594:190-203. [PMID: 25446445 DOI: 10.1016/j.brainres.2014.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 11/04/2014] [Accepted: 11/06/2014] [Indexed: 11/25/2022]
Abstract
Interactions of opioid receptors with other receptor families can be made use of to improve analgesia and reduce adverse effects of opioid analgesics. We investigated interactions of the α2-adrenergic receptor (α2AR) with opioid receptors of the mu (MOR) and delta (DOR) types in the spinal dorsal horn in an animal model of neuropathic pain induced by spinal nerve ligation. Nine days after nerve injury, immunoreactivity for the α2AR subtype A (α2AAR) was increased both in tissue homogenates and at pre- and post-synaptic sites in transverse sections. The efficacy of spinally administered α2AAR agonist guanfacine at reducing C-fiber-evoked field potentials was increased in nerve-ligated rats. This reducing effect was impaired by simultaneous administration of DOR antagonist naltrindole, but not MOR antagonist CTOP, suggesting that concurrent DOR activation was required for α2AAR-mediated inhibition. While DOR agonist deltorphin II and MOR agonist DAMGO both effectively depressed C-fiber-evoked spinal field potentials, DOR- but not MOR-mediated depression was enhanced by subclinical guanfacine. In conscious, nerve-ligated rats, chronically administered deltorphin II produced stable thermal and mechanical antinociception over the 9 following days after nerve injury without apparent signs of habituation. Such an effect was dramatically enhanced by co-administration of a low dose of guanfacine, which reversed thermal and mechanical thresholds to levels near those prior to injury. The results suggest that spinal, α2AAR-mediated antinociception is increased after nerve injury and based on DOR co-activation. We demonstrate in vivo that α2AAR/DOR interaction can be exploited to provide effective behavioral antinociception during neuropathic pain.
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Affiliation(s)
- Zigor Aira
- Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country, PO Box 699, 48080 Bilbao, Spain
| | - Teresa Barrenetxea
- Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country, PO Box 699, 48080 Bilbao, Spain
| | - Itsaso Buesa
- Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country, PO Box 699, 48080 Bilbao, Spain
| | - Jon Jatsu Azkue
- Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country, PO Box 699, 48080 Bilbao, Spain.
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19
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Sachan P, Kumar N, Sharma J. Intrathecal clonidine with hyperbaric bupivacaine administered as a mixture and sequentially in caesarean section: A randomised controlled study. Indian J Anaesth 2014; 58:287-92. [PMID: 25024471 PMCID: PMC4090994 DOI: 10.4103/0019-5049.135039] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND AND AIMS Mixing adjuvants with hyperbaric bupivacaine in a single syringe before injecting the drugs intrathecally is an age old practice. In doing so, the density of the hyperbaric solution and also of the adjuvant drugs may be altered, thus affecting the spread of drugs. Administering local anaesthetic and the adjuvants separately may minimise the effect of the changes in densities. We aimed to compare block characteristics, intraoperative haemodynamics and post-operative pain relief in parturients undergoing caesarean section (CS) after administering hyperbaric bupivacaine and clonidine intrathecally as a mixture and sequentially. METHODS In this single-blind prospective randomised controlled study at a tertiary care centre from 2010 to 12, 60 full-term parturients scheduled for elective CSs were divided into two groups on the basis of technique of intrathecal drug administration. Group M received mixture of clonidine (75 mcg) and hyperbaric bupivacaine 0.5% (10 mg) intrathecally, whereas Group B received clonidine (75 mcg) followed by hyperbaric bupivacaine 0.5% (10 mg) through separate syringes. Observational descriptive statistics, analysis of variance test, Wilcoxon test and Chi-square test were used as applicable. RESULTS Duration of analgesia was significantly longer in Group B (474.33 ± 20.79 min) in which the drug was given sequentially than in Group M (337 ± 18.22 min). Furthermore, the time to achieve highest sensory block and complete motor block was significantly less in Group B without any major haemodynamic instability and neonatal outcome. CONCLUSIONS When clonidine and hyperbaric bupivacaine were administered in a sequential manner, block characteristics improved significantly compared to the administration of the mixture of the two drugs.
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Affiliation(s)
- Prachee Sachan
- Department of Anaeasthesia, Himalayan Institute of Medical Sciences, Doiwala, Dehradun, Uttarakhand, India
| | - Nidhi Kumar
- Department of Anaeasthesia, Himalayan Institute of Medical Sciences, Doiwala, Dehradun, Uttarakhand, India
| | - Jp Sharma
- Department of Anaeasthesia, Himalayan Institute of Medical Sciences, Doiwala, Dehradun, Uttarakhand, India
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20
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Fan QQ, Li L, Wang WT, Yang X, Suo ZW, Hu XD. Activation of α2 adrenoceptors inhibited NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice with inflammatory pain. Neuropharmacology 2014; 77:185-92. [DOI: 10.1016/j.neuropharm.2013.09.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 08/17/2013] [Accepted: 09/23/2013] [Indexed: 01/06/2023]
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Abstract
In the last decade, preclinical investigations of electroacupuncture mechanisms on persistent tissue injury (inflammatory), nerve injury (neuropathic), cancer, and visceral pain have increased. These studies show that electroacupuncture activates the nervous system differently in health than in pain conditions, alleviates both sensory and affective inflammatory pain, and inhibits inflammatory and neuropathic pain more effectively at 2 to 10 Hz than at 100 Hz. Electroacupuncture blocks pain by activating a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms. These include opioids, which desensitize peripheral nociceptors and reduce proinflammatory cytokines peripherally and in the spinal cord, and serotonin and norepinephrine, which decrease spinal N-methyl-D-aspartate receptor subunit GluN1 phosphorylation. Additional studies suggest that electroacupuncture, when combined with low dosages of conventional analgesics, provides effective pain management which can forestall the side effects of often-debilitating pharmaceuticals.
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Affiliation(s)
- Ruixin Zhang
- Assistant Professor, Center for Integrative Medicine, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Lixing Lao
- Professor, Center for Integrative Medicine, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Ke Ren
- Professor, Department of Neural and Pain Sciences, Dental School, University of Maryland, Baltimore, Maryland
| | - Brian M. Berman
- Professor, Center for Integrative Medicine, School of Medicine, University of Maryland, Baltimore, Maryland
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Deumens R, Steyaert A, Forget P, Schubert M, Lavand’homme P, Hermans E, De Kock M. Prevention of chronic postoperative pain: Cellular, molecular, and clinical insights for mechanism-based treatment approaches. Prog Neurobiol 2013; 104:1-37. [DOI: 10.1016/j.pneurobio.2013.01.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 01/15/2013] [Accepted: 01/31/2013] [Indexed: 01/13/2023]
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Central α-adrenoceptors contribute to mustard oil-induced central sensitization in the rat medullary dorsal horn. Neuroscience 2013; 236:244-52. [PMID: 23333675 DOI: 10.1016/j.neuroscience.2013.01.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 12/22/2012] [Accepted: 01/03/2013] [Indexed: 11/22/2022]
Abstract
Our previous studies have demonstrated that application of the inflammatory irritant mustard oil (MO) to the tooth pulp produces trigeminal central sensitization that includes increases in mechanoreceptive field size and responses to noxious stimuli and decrease in activation threshold in brainstem nociceptive neurons of trigeminal subnucleus caudalis (the medullary dorsal horn, MDH). The aim of the present study was to test if central noradrenergic processes are involved in the central sensitization of MDH neurons and if α1-adrenoceptors or α2-adrenoceptors or both are involved. In urethane/α-chloralose-anesthetized rats, the activity of extracellularly recorded and functionally identified single nociceptive neurons in the MDH was studied. Continuous intrathecal (i.t.) superfusion of the adrenergic modulator guanethidine and α-adrenoceptor blocker phentolamine or selective α1-adrenoceptor antagonist prazosin over the medulla strongly attenuated all three MO-induced parameters of central sensitization in the MDH nociceptive neurons, compared to phosphate-buffered saline (as vehicle control). In contrast, i.t. superfusion of the selective α2-adrenoceptor antagonist yohimbine had little effect on the mechanoreceptive field expansion and the decreased mechanical activation threshold, and indeed facilitated responses to noxious stimuli of sensitized nociceptive neurons. Superfusion of each of the four chemicals alone did not affect baseline nociceptive neuronal properties. These findings provide the first documentation of the involvement of central noradrenergic processes in MDH in the development of the central sensitization, and that α1- and α2-adrenoceptors may be differentially involved.
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Jeong Y, Moes JR, Wagner M, Holden JE. The posterior hypothalamus exerts opposing effects on nociception via the A7 catecholamine cell group in rats. Neuroscience 2012; 227:144-53. [PMID: 23036619 DOI: 10.1016/j.neuroscience.2012.09.058] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 09/19/2012] [Accepted: 09/22/2012] [Indexed: 01/16/2023]
Abstract
Stimulation of the posterior hypothalamic area (PH) produces antinociception in rats and humans, but the precise mechanisms are unknown. The PH forms anatomical connections with the parabrachial area, which contains the pontine A7 catecholamine cell group, a group of spinally projecting noradrenergic neurons known to produce antinociception in the dorsal horn. The aim of the present study was to determine whether PH-induced antinociception is mediated in part through connections with the A7 cell group in female Sprague-Dawley rats, as measured by the tail flick and foot withdrawal latency. Stimulation of the PH with the cholinergic agonist carbachol (125 nmol) produced antinociception that was blocked by pretreatment with atropine sulfate. Intrathecal injection of the α(2)-adrenoceptor antagonist yohimbine reversed PH-induced antinociception, but the α(1)-adrenoceptor antagonist WB4101 facilitated antinociception. Intrathecal injection of normal saline had no effect. In a separate experiment, cobalt chloride, which reversibly arrests synaptic activity, was microinjected into the A7 cell group and blocked PH-induced antinociception. These findings provide evidence that the PH modulates nociception in part through connections with the A7 catecholamine cell group through opposing effects. Antinociception occurs from actions at α(2)-adrenoceptors in the dorsal horn, while concurrent hyperalgesia occurs from actions of norepinephrine at α(1)-adrenoceptors. This hyperalgesic response likely attenuates antinociception from PH stimulation.
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Affiliation(s)
- Y Jeong
- College of Nursing Science, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu, Seoul 130-701, Korea.
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Zhang Y, Zhang RX, Zhang M, Shen XY, Li A, Xin J, Ren K, Berman BM, Tan M, Lao L. Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model: involvement of distinct spinal serotonin and norepinephrine receptor subtypes. Br J Anaesth 2012; 109:245-52. [PMID: 22628394 PMCID: PMC3393079 DOI: 10.1093/bja/aes136] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2012] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Although acupuncture analgesia is well documented, its mechanisms have not been thoroughly clarified. We previously showed that electroacupuncture (EA) activates supraspinal serotonin- and norepinephrine-containing neurones that project to the spinal cord. This study investigates the involvement of spinal alpha(2)-adrenoceptors (α2-ARs) and 5-hydroxytryptamine (serotonin) receptors (5-HTRs) in EA effects on an inflammatory pain rat model. METHODS Inflammatory hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08 ml) into the plantar surface of one hind paw and assessed by paw withdrawal latency (PWL) to a noxious thermal stimulus. The selective α2a-AR antagonist BRL-44408, α2b-AR antagonist imiloxan hydrochloride, 5-HT2B receptor (5-HT2BR) antagonist SB204741, 5-HT3R antagonist LY278584, or 5-HT1AR antagonists NAN-190 hydrobromide, or WAY-100635 were intrathecally administered 20 min before EA or sham EA, which was given 2 h post-CFA at acupoint GB30. RESULTS EA significantly increased PWL compared with sham [7.20 (0.46) vs 5.20 (0.43) s]. Pretreatment with α2a-AR [5.35 (0.45) s] or 5-HT1AR [5.22 (0.38) s] antagonists blocked EA-produced anti-hyperalgesia; α2b-AR, 5-HT2BR, and 5-HT3R antagonist pretreatment did not. Sham plus these antagonists did not significantly change PWL compared with sham plus vehicle, indicating that the antagonists had little effect on PWL. Immunohistochemical staining demonstrated that α2a-ARs are on primary afferents and 5-HT1ARs are localized in N-methyl-d-aspartic acid (NMDA) subunit NR1-containing neurones in the spinal dorsal horn. CONCLUSIONS The data show that α2a-ARs and 5-HT1ARs are involved in the EA inhibition of inflammatory pain and that the NMDA receptors are involved in EA action.
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MESH Headings
- Adrenergic alpha-2 Receptor Antagonists/pharmacology
- Animals
- Disease Models, Animal
- Electroacupuncture/methods
- Freund's Adjuvant
- Hot Temperature
- Hyperalgesia/chemically induced
- Hyperalgesia/metabolism
- Hyperalgesia/prevention & control
- Male
- Pain Measurement/methods
- Rats
- Rats, Sprague-Dawley
- Reaction Time/drug effects
- Reaction Time/physiology
- Receptors, Adrenergic, alpha-2/metabolism
- Receptors, Adrenergic, alpha-2/physiology
- Receptors, Serotonin, 5-HT1/metabolism
- Receptors, Serotonin, 5-HT1/physiology
- Serotonin 5-HT1 Receptor Antagonists/pharmacology
- Spinal Cord/metabolism
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Affiliation(s)
- Y. Zhang
- Center for Integrative Medicine, School of Medicine, University of Maryland, 685 W. Baltimore St. MSTF, Rm 8-22, Baltimore, MD 21201, USA
- Department of Neurobiology, Shanxi Medical University, Taiyuan 030001, Shanxi, P.R. China
| | - R. X. Zhang
- Center for Integrative Medicine, School of Medicine, University of Maryland, 685 W. Baltimore St. MSTF, Rm 8-22, Baltimore, MD 21201, USA
| | - M. Zhang
- Center for Integrative Medicine, School of Medicine, University of Maryland, 685 W. Baltimore St. MSTF, Rm 8-22, Baltimore, MD 21201, USA
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - X. Y. Shen
- Acupuncture College, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - A. Li
- Center for Integrative Medicine, School of Medicine, University of Maryland, 685 W. Baltimore St. MSTF, Rm 8-22, Baltimore, MD 21201, USA
| | - J. Xin
- Center for Integrative Medicine, School of Medicine, University of Maryland, 685 W. Baltimore St. MSTF, Rm 8-22, Baltimore, MD 21201, USA
| | - K. Ren
- Department of Neural and Pain Sciences, Dental School, University of Maryland, Baltimore, MD 21201, USA
| | - B. M. Berman
- Center for Integrative Medicine, School of Medicine, University of Maryland, 685 W. Baltimore St. MSTF, Rm 8-22, Baltimore, MD 21201, USA
| | - M. Tan
- Division of Biostatistics, University of Maryland Greenebaum Cancer Center, Baltimore, MD 21201, USA
| | - L. Lao
- Center for Integrative Medicine, School of Medicine, University of Maryland, 685 W. Baltimore St. MSTF, Rm 8-22, Baltimore, MD 21201, USA
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Deer TR, Prager J, Levy R, Rathmell J, Buchser E, Burton A, Caraway D, Cousins M, De Andrés J, Diwan S, Erdek M, Grigsby E, Huntoon M, Jacobs MS, Kim P, Kumar K, Leong M, Liem L, McDowell GC, Panchal S, Rauck R, Saulino M, Sitzman BT, Staats P, Stanton-Hicks M, Stearns L, Wallace M, Willis KD, Witt W, Yaksh T, Mekhail N. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 2012; 15:436-64; discussion 464-6. [PMID: 22748024 DOI: 10.1111/j.1525-1403.2012.00476.x] [Citation(s) in RCA: 155] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The use of intrathecal (IT) infusion of analgesic medications to treat patients with chronic refractory pain has increased since its inception in the 1980s, and the need for clinical research in IT therapy is ongoing. The Polyanalgesic Consensus Conference (PACC) panel of experts convened in 2000, 2003, and 2007 to make recommendations on the rational use of IT analgesics based on preclinical and clinical literature and clinical experiences. METHODS The PACC panel convened again in 2011 to update the standard of care for IT therapies to reflect current knowledge gleaned from literature and clinical experience. A thorough literature search was performed, and information from this search was provided to panel members. Analysis of published literature was coupled with the clinical experience of panel members to form recommendations regarding the use of IT analgesics to treat chronic pain. RESULTS After a review of literature published from 2007 to 2011 and discussions of clinical experience, the panel created updated algorithms for the rational use of IT medications for the treatment of neuropathic pain and nociceptive pain. CONCLUSIONS The advent of new algorithmic tracks for neuropathic and nociceptive pain is an important step in improving patient care. The panel encourages continued research and development, including the development of new drugs, devices, and safety recommendations to improve the care of patients with chronic pain.
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Aguado D, Abreu M, Benito J, Garcia-Fernandez J, Gómez de Segura IA. The effects of gabapentin on acute opioid tolerance to remifentanil under sevoflurane anesthesia in rats. Anesth Analg 2012; 115:40-5. [PMID: 22523419 DOI: 10.1213/ane.0b013e3182542727] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Tolerance to remifentanil during sevoflurane anesthesia may blunt the ability of this drug to reduce anesthetic requirements. Gabapentin has been shown to be effective in reducing postoperative narcotic usage, a reduction that may be associated with a reduction in opioid-induced tolerance and hyperalgesia. We sought to determine whether gabapentin might prevent the observed acute opioid tolerance (AOT) produced by remifentanil in sevoflurane minimum alveolar concentration (MAC). METHODS Wistar rats were anesthetized with sevoflurane and the effects of gabapentin alone on sevoflurane MAC were determined at doses of 150 and 300 mg · kg(-1). In a second experiment, gabapentin 300 mg · kg(-1) was administered before remifentanil (120 and 240 μg · kg(-1) · h(-1)). The MAC was determined before gabapentin administration and 3 more times at 1.5-hour intervals after drug administration to assess AOT. MAC was determined from intratracheal gas samples using a sidestream gas analyzer; tail clamping was used as a supramaximal stimulus. Statistical analysis was performed with the 1-way analysis of variance test. RESULTS Remifentanil reduced MAC (2.5 ± 0.2%) by 16% ± 5% and 36% ± 6% (120 and 240 μg · kg(-1) · h(-1), respectively, P < 0.01) with a further reduction produced by coadministration with gabapentin 300 mg · kg(-1) to 39% ± 12% and 62% ± 14%, respectively (P < 0.01 versus remifentanil alone). Gabapentin given alone at 150 and 300 mg · kg(-1) reduced MAC by 26% (both doses, P < 0.01). AOT was observed with remifentanil and characterized by a lower degree of MAC reduction, approximately 1.5 hours later (P < 0.05). However, when remifentanil was administered with gabapentin, the AOT to remifentanil was not observed (P > 0.05). CONCLUSIONS Gabapentin reduced the sevoflurane MAC and enhanced the MAC reduction produced by remifentanil. This enhancement may limit AOT in rats.
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Affiliation(s)
- Delia Aguado
- Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Avda. Puerta de Hierro s/n, 28040 Madrid, Spain
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Huang YN, Tsai RY, Lin SL, Chien CC, Cherng CH, Wu CT, Yeh CC, Wong CS. Amitriptyline attenuates astrocyte activation and morphine tolerance in rats: Role of the PSD-95/NR1/nNOS/PKCγ signaling pathway. Behav Brain Res 2012; 229:401-11. [DOI: 10.1016/j.bbr.2012.01.044] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Revised: 01/19/2012] [Accepted: 01/23/2012] [Indexed: 12/13/2022]
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Zheng Y, Cui S, Liu Y, Zhang J, Zhang W, Zhang J, Gu X, Ma Z. Dexmedetomidine prevents remifentanil-induced postoperative hyperalgesia and decreases spinal tyrosine phosphorylation of N-methyl-d-aspartate receptor 2B subunit. Brain Res Bull 2012; 87:427-31. [DOI: 10.1016/j.brainresbull.2012.01.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 01/07/2012] [Accepted: 01/09/2012] [Indexed: 12/19/2022]
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Kang SY, Roh DH, Yoon SY, Moon JY, Kim HW, Lee HJ, Beitz AJ, Lee JH. Repetitive treatment with diluted bee venom reduces neuropathic pain via potentiation of locus coeruleus noradrenergic neuronal activity and modulation of spinal NR1 phosphorylation in rats. THE JOURNAL OF PAIN 2012; 13:155-66. [PMID: 22217441 DOI: 10.1016/j.jpain.2011.10.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 10/14/2011] [Accepted: 10/26/2011] [Indexed: 11/25/2022]
Abstract
UNLABELLED We previously demonstrated that a single injection of diluted bee venom (DBV) temporarily alleviates thermal hyperalgesia, but not mechanical allodynia, in neuropathic rats. The present study was designed to determine whether repetitive injection of DBV produces more potent analgesic effects on neuropathy-induced nociception and whether those effects are associated with increased neuronal activity in the locus coeruleus (LC) and with the suppression of spinal NMDA receptor NR1 subunit phosphorylation (pNR1). DBV (.25 mg/kg) was administered subcutaneously twice a day for 2 weeks beginning on day 15 post-chronic constrictive injury surgery. Pain responses were examined and potential changes in LC Fos expression and spinal pNR1 expression were determined. Repetitive DBV administration significantly reduced mechanical allodynia, as well as thermal hyperalgesia. The activity of LC noradrenergic neurons was increased and spinal pNR1 expression was significantly suppressed by repetitive DBV as compared with those of vehicle or single DBV injection. These suppressive effects of repetitive DBV on neuropathic pain and spinal pNR1 were prevented by intrathecal pretreatment of idazoxan, an alpha-2 adrenoceptor antagonist. These results indicate that repetitive DBV produces potent analgesic effects on neuropathic pain and this is associated with the activation of the LC noradrenergic system and with a reduction in spinal pNR1. PERSPECTIVE The results of current study demonstrate that repetitive administration of DBV significantly suppresses neuropathic pain. Furthermore, this study provides mechanistic information that repetitive treatment of DBV can produce more potent analgesic effect than single DBV treatment, indicating a potential novel strategy for the management of chronic pain.
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Affiliation(s)
- Suk-Yun Kang
- Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea
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Ramasubbu C, Gupta A. Pharmacological Treatment of Opioid-Induced Hyperalgesia: A Review of the Evidence. J Pain Palliat Care Pharmacother 2011; 25:219-30. [DOI: 10.3109/15360288.2011.589490] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Takami K, Fujita-Hamabe W, Harada S, Tokuyama S. Aβ and Aδ but not C-fibres are involved in stroke related pain and allodynia: an experimental study in mice. J Pharm Pharmacol 2011; 63:452-6. [DOI: 10.1111/j.2042-7158.2010.01231.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Abstract
Objectives
Cerebral ischaemia is a leading cause of death and disability, including severe complications such as memory disturbance, palsy, and spasticity. Central post-stroke pain (CPSP) is a complication of cerebral ischaemia, and is characterized clinically by spontaneous pain and attacks of allodynia and dysaesthesia. However, the detailed mechanisms of CPSP are not well established. Herein, we have examined alterations of the current stimulus threshold of primary afferent neurons or the nociceptive threshold against mechanical stimuli in mice receiving left middle cerebral artery occlusion (MCAO).
Methods
Alterations of current stimulus threshold and the development of mechanical allodynia in hind paws were measured after MCAO using a Neurometer and the von Frey filament test, respectively.
Key findings
Development of cerebral infarction was clearly observed on day 1 and day 3 after MCAO. For the estimation of current stimulus threshold measured by the Neurometer, the sensitivity of Aδ and Aβ fibres (at 2000 and 250 Hz stimulation, respectively) was significantly increased on day 3 after MCAO, while that of C fibres (at 5 Hz stimulation) was unaltered. In addition, the paw withdrawal threshold of the left hind paw as measured by the von Frey filament test was significantly decreased on day 1 and day 3 after MCAO when compared with day 0, while that in the right hind paw was not different.
Conclusions
The data suggested the development of bilateral hyperaesthesia in this model. Further, mechanical allodynia developed in the ipsilateral side to the MCAO. Potentially, myelinated A fibre-specific hypersensitization after stroke may have contributed to these symptoms.
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Affiliation(s)
- Kazunori Takami
- Department of Clinical Pharmacy, Kobe Gakuin University, School of Pharmaceutical Sciences, Kobe, Japan
| | - Wakako Fujita-Hamabe
- Department of Clinical Pharmacy, Kobe Gakuin University, School of Pharmaceutical Sciences, Kobe, Japan
| | - Shinichi Harada
- Department of Clinical Pharmacy, Kobe Gakuin University, School of Pharmaceutical Sciences, Kobe, Japan
| | - Shogo Tokuyama
- Department of Clinical Pharmacy, Kobe Gakuin University, School of Pharmaceutical Sciences, Kobe, Japan
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Abstract
The elusiveness of neuropathic pain mechanisms is a major impediment in developing effective clinical treatments. Here we show that peripheral nerve injury decreased agrin expression in the ipsilateral spinal dorsal horn of rats displaying tactile allodynia. SCP1, an acetaminophen analog, suppressed allodynia and promoted agrin upregulation. Preemptive treatment with SCP1 also upregulated agrin, thereby preventing neuropathic pain development. Expression of 50 kDa agrin delivered by adeno-associated virus into the dorsal horn also suppressed allodynia and hyperalgesia. Allodynia suppression was a consequence of serine residue 896/897 phosphorylation of NMDA receptor NR1 subunits in the GABA interneurons of the dorsal horn. Agrin silencing by small interference RNA, administered with either AAV-Ag50 vector or SCP1, blocked allodynia suppression, agrin upregulation, and NR1 phosphorylation. In conclusion, 50 kDa agrin modulates neuropathic pain through NR1 phosphorylation in GABA neurons. This mechanism may open new approaches for treating not only neuropathic pain, but also epilepsy, tremors, and spasticity.
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Yoon SY, Roh DH, Seo HS, Kang SY, Moon JY, Song S, Beitz AJ, Lee JH. An increase in spinal dehydroepiandrosterone sulfate (DHEAS) enhances NMDA-induced pain via phosphorylation of the NR1 subunit in mice: involvement of the sigma-1 receptor. Neuropharmacology 2010; 59:460-7. [PMID: 20600171 DOI: 10.1016/j.neuropharm.2010.06.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2010] [Revised: 06/08/2010] [Accepted: 06/15/2010] [Indexed: 10/19/2022]
Abstract
Our laboratory has recently demonstrated that an increase in the spinal neurosteroid, dehydroepiandrosterone sulfate (DHEAS) facilitates nociception via the activation of sigma-1 receptors and/or the allosteric inhibition GABA(A) receptors. Several lines of evidence have suggested that DHEAS positively modulates N-methyl-d-aspartate (NMDA) receptor activity within the central nervous system. Moreover, we have demonstrated that the activation of sigma-1 receptors increases NMDA receptor activity. Since NMDA receptors play a key role in the enhancement of pain perception, the present study was designed to determine whether spinally administered DHEAS modulates NMDA receptor-mediated nociceptive activity and whether this effect is mediated by sigma-1 or GABA(A) receptors. Intrathecal (i.t.) DHEAS was found to significantly potentiate i.t. NMDA-induced spontaneous pain behaviors. Subsequent immunohistochemical analysis demonstrated that i.t. DHEAS also increased protein kinase C (PKC)- and protein kinase A (PKA)-dependent phosphorylation of the NMDA receptor subunit NR1 (pNR1), which was used as a marker of NMDA receptor sensitization. The sigma-1 receptor antagonist, BD-1047, but not the GABA(A) receptor agonist, muscimol, dose-dependently suppressed DHEAS's facilitatory effect on NMDA-induced nociception and pNR1 expression. In addition, pretreatment with either a PKC or PKA blocker significantly reduced the facilitatory effect of DHEAS on NMDA-induced nociception. Conversely the GABA(A) receptor antagonist, bicuculline did not affect NMDA-induced pain behavior or pNR1 expression. The results of this study suggest that the DHEAS-induced enhancement of NMDA-mediated nociception is dependent on an increase in PKC- and PKA-dependent pNR1. Moreover, this effect of DHEAS on NMDA receptor activity is mediated by the activation of spinal sigma-1 receptors and not through the inhibition of GABA(A) receptors.
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Affiliation(s)
- Seo-Yeon Yoon
- Department of Anesthesiology and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Norepinephrine can act via alpha(2)-adrenoceptors to reduce the hyper-excitability of spinal dorsal horn neurons following chronic nerve injury. J Formos Med Assoc 2010; 109:438-45. [PMID: 20610145 DOI: 10.1016/s0929-6646(10)60075-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2009] [Revised: 07/08/2009] [Accepted: 08/11/2009] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/PURPOSE Rats display behavioral signs of neuropathic pain lasting for months in the chronic constriction injury (CCI) model. During intrathecal anesthesia, the administered drugs mainly diffuse directly into the superficial neurons in the spinal dorsal horn. This study aimed to investigate the effect of bath application of norepinephrine on whole cell patch clamp recordings from spinal cord slices of CCI rats with allodynia. METHODS An assessment of paw withdrawal threshold in response to mechanical stimulation was performed on the operated side on the day before surgery and was repeated after recovery from anesthesia and on the 7(th) and 14(th) days after surgery. Spinal cord slice preparations containing dorsal horn neurons were obtained from both sham-operated rats and CCI rats (after the 14(th) postoperative day behavior test). RESULTS Compared with normal controls, CCI rats had significantly lower levels of both hyperpolarization and spike threshold in single action potentials recorded from lamina I and II neurons of the spinal dorsal horn. In contrast, a series of action potential recordings showed that the percentage of spiking neurons of the spinal dorsal horn of CCI rats were significantly higher than those of normal controls. The CCI-induced reduction in hyperpolarization, as well as the increased numbers of spinal dorsal horn spiking neurons could be significantly reduced by norepinephrine application. The norepinephrine-induced increased hyperpolarization and input resistance could be abolished by the application of an alpha(2)-adrenoceptor antagonist (idazoxan; 200 nM). CONCLUSION The results suggest that chronic nerve injury may induce neuropathic pain by increasing the excitability of spinal dorsal horn neurons. This excitability can be reduced by norepinephrine.
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Daulhac L, Maffre V, Mallet C, Etienne M, Privat AM, Kowalski-Chauvel A, Seva C, Fialip J, Eschalier A. Phosphorylation of spinal N-methyl-d-aspartate receptor NR1 subunits by extracellular signal-regulated kinase in dorsal horn neurons and microglia contributes to diabetes-induced painful neuropathy. Eur J Pain 2010; 15:169.e1-169.e12. [PMID: 20594879 DOI: 10.1016/j.ejpain.2010.06.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 05/10/2010] [Accepted: 06/01/2010] [Indexed: 01/15/2023]
Abstract
The N-methyl-d-aspartate receptor (NMDAR) contributes to central sensitization in the spinal cord, a phenomenon which comprises various pathophysiological mechanisms responsible for neuropathic pain-like signs in animal models. NMDAR function is modulated by post-translational modifications including phosphorylation, and this is proposed to underlie its involvement in the production of pain hypersensitivity. As in diabetic patients, streptozotocin-induced diabetic rats exhibit or not somatic mechanical hyperalgesia; these rats were named DH and DNH respectively. At three weeks of diabetes, we present evidence that somatic mechanical hyperalgesia was correlated with an enhanced phosphorylation of the NMDAR NR1 subunit (pNR1) in the rat spinal cord. This increase was not found in normal and DNH rats, suggesting that this regulation was specific to hyperalgesia. Double immunofluorescence studies revealed that the numbers of pNR1-immunoreactive neurons and microglial cells were significantly increased in all laminae (I-II and III-VI) of the dorsal horn from DH animals. Western-blots analysis showed no change in NR1 protein levels, whatever the behavioural and glycemic status of the animals. Chronic intrathecal treatment (5μg/rat/day for 7days) by U0126 and MK801, which blocked MEK (an upstream kinase of extracellular signal-regulated protein kinase: ERK) and the NMDAR respectively, simultaneously suppressed somatic mechanical hyperalgesia developed by diabetic rats and decreased pNR1. These results indicate for the first time that increased expression of pNR1 is regulated by ERK and the NMDAR via a feedforward mechanism in spinal neurons and microglia and represents one mechanism involved in central sensitization and somatic mechanical hyperalgesia after diabetes.
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Affiliation(s)
- Laurence Daulhac
- Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, Laboratoire de Pharmacologie, Faculté de Pharmacie, Clermont-Ferrand, France.
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Gallaher ZR, Larios RM, Ryu V, Sprunger LK, Czaja K. Recovery of viscerosensory innervation from the dorsal root ganglia of the adult rat following capsaicin-induced injury. J Comp Neurol 2010; 518:3529-40. [DOI: 10.1002/cne.22412] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Roh DH, Seo HS, Yoon SY, Song S, Han HJ, Beitz AJ, Lee JH. Activation of Spinal α-2 Adrenoceptors, but Not μ-Opioid Receptors, Reduces the Intrathecal N-Methyl-d-Aspartate-Induced Increase in Spinal NR1 Subunit Phosphorylation and Nociceptive Behaviors in the Rat. Anesth Analg 2010; 110:622-9. [DOI: 10.1213/ane.0b013e3181c8afc1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Abstract
This paper is the 31st consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2008 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).
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Affiliation(s)
- Richard J Bodnar
- Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, 65-30 Kissena Blvd, Flushing, NY 11367, United States.
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Intrathecal administration of clonidine attenuates spinal neuroimmune activation in a rat model of neuropathic pain with existing hyperalgesia. Eur J Pharmacol 2009; 614:38-43. [PMID: 19397906 DOI: 10.1016/j.ejphar.2009.04.044] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2009] [Revised: 04/13/2009] [Accepted: 04/20/2009] [Indexed: 11/23/2022]
Abstract
Central neuroimmune activation contributes to the initiation and maintenance of neuropathic pain after nerve injury. The current study was aimed to examine the modulation of neuroimmune activation in the spinal cord by the alpha(2) adrenoceptor agonist, clonidine, in a rat model of neuropathic pain induced by partial sciatic nerve ligation (PSNL). Animals were randomly assigned into 6 groups: sham-operation with 20 microg clonidine or saline; and PSNL with clonidine (5, 10, and 20 microg) or saline. Fourteen days post-operation, various doses of clonidine or saline were injected intrathecally. The paw pressure threshold and paw withdrawal latencies were measured before and at 30, 60, 90, and 120 min after the injection of clonidine. Glial activation markers such as macrophage antigen complex-1 (mac-1) and glial fibrillary acidic protein (GFAP), interleukin (IL)-1beta and IL-6, nuclear factor-kappa B (NF-kappaB) activation, and p-p38 mitogen-activated protein kinase (MAPK) activation in the lumbar spinal cord were determined as well. Administration of clonidine resulted in a dose-dependent attenuation in PSNL-induced mechanical and thermal hyperalgesia. Furthermore, clonidine could markedly inhibit neuroimmune activation characterized by glial activation, production of cytokines, NF-kappaB activation as well as p38 activation. The antihyperalgesic effect of intrathecal clonidine in rats receiving PSNL might partly attribute to the inhibition of neuroimmune activation associated with the maintenance of neuropathic pain.
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Li SQ, Xing YL, Chen WN, Yue SL, Li L, Li WB. Activation of NMDA receptor is associated with up-regulation of COX-2 expression in the spinal dorsal horn during nociceptive inputs in rats. Neurochem Res 2009; 34:1451-63. [PMID: 19337831 DOI: 10.1007/s11064-009-9932-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2008] [Accepted: 02/04/2009] [Indexed: 11/29/2022]
Abstract
Cyclooxygenases-2 (COX-2) in the spinal dorsal horn is up-regulated and plays an important role in pain and hyperalgesia induced by nociceptive stimulation. The mechanisms involved in the up-regulation of spinal COX-2 during nociceptive stimulation are yet not well understood. Because the important role of NMDA and its receptor in transmission of nociceptive information in the spinal cord, activation of the spinal NMDA receptor might contribute to the up-regulation of spinal COX-2 expression. The present study was undertaken to demonstrate the above hypothesis by observing changes of COX-2 expression in the spinal dorsal horn in rats subjected to formalin test and intrathecal administration of NMDA, a selective NMDA receptor agonist, in conditions with or without presence of MK-801, an antagonist of NMDA receptor, using methods of Western blotting, reverse transcription polymerase chain reaction and immunohistochemistry. The results showed that intrathecal injection of MK-801, a noncompetitive antagonist of NMDA receptor, significantly suppressed the up-regulation of the COX-2 expression and characteristic pain behavior responses evoked in formalin test. Whereas, intrathecal injection of NMDA significantly up-regulated the expression of COX-2 in the spinal dorsal horn in a time course corresponding to that of nociceptive behavioral responses elicited by the intrathecal NMDA administration. In addition, the up-regulation of the COX-2 expression induced by the intrathecal NMDA was dose-dependent and blocked by prior administration of MK-801. These findings proved that activation of NMDA receptor is associated with the up-regulation of COX-2 expression in the spinal dorsal horn during nociceptive stimulation in rats.
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Affiliation(s)
- Shu-Qin Li
- Department of Pathophysiology, Institute of Basic Medicine, Hebei Medical University, 361 Zhongshan East Road, 050017, Shijiazhuang, People's Republic of China
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Yoon SY, Roh DH, Kwon YB, Kim HW, Seo HS, Han HJ, Lee HJ, Beitz AJ, Lee JH. Acupoint stimulation with diluted bee venom (apipuncture) potentiates the analgesic effect of intrathecal clonidine in the rodent formalin test and in a neuropathic pain model. THE JOURNAL OF PAIN 2008; 10:253-63. [PMID: 19010737 DOI: 10.1016/j.jpain.2008.09.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2008] [Revised: 08/18/2008] [Accepted: 09/02/2008] [Indexed: 10/21/2022]
Abstract
UNLABELLED Although intrathecal (i.t.) administration of the alpha(2)-adrenoceptor agonist clonidine has a pronounced analgesic effect, the clinical use of clonidine is limited by its side effects. Previously, our laboratory has demonstrated that the subcutaneous injection of diluted bee venom (DBV) into an acupoint (termed apipuncture) produces significant analgesic effect in various pain animal models. The present study was designed to examine whether DBV injection into the Zusanli acupoint (ST-36) could enhance lower-dose clonidine-induced analgesic effects without the development of hypotension, bradycardia, or sedation. In the mouse formalin test, DBV injection produced a dramatic leftward shift in the dose-response curve for clonidine-induced analgesia. In a rat neuropathic pain model i.t. clonidine dose dependently suppressed chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia, and this clonidine-induced analgesic effect was significantly potentiated by apipuncture pretreatment. DBV apipuncture alone or in combination with a low dose of i.t. clonidine produced an analgesic effect similar to that of the high dose of clonidine, but without significant side effects. The analgesic effect produced by the combination of i.t. clonidine and apipuncture was completely blocked by pretreatment with an alpha(2)-adrenoceptor antagonist. These data show that DBV-apipuncture significantly enhances clonidine-induced analgesia and suggest that a combination of low dose clonidine with acupuncture therapy represents a novel strategy for pain management that could eliminates clonidine's side effects. PERSPECTIVE This study demonstrated that intrathecal clonidine-induced analgesia is significantly enhanced when it is combined with chemical acupuncture treatment. The administration of low-dose clonidine in combination with acupuncture produced a potent analgesic effect without significant side effects and thus represents a potential novel strategy for the management of chronic pain.
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Affiliation(s)
- Seo-Yeon Yoon
- Department of Veterinary Physiology, College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul, South Korea
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