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Landinger A, Zablotski Y, Knubben-Schweizer G, Tschoner T. Comparison of plasma substance P concentrations in the blood of healthy male and female German Simmental calves. BMC Vet Res 2024; 20:226. [PMID: 38790004 PMCID: PMC11127320 DOI: 10.1186/s12917-024-04010-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 04/09/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND The recognition of pain is a major problem in cattle, as they are stoic animals which strongly mask their pain. Among objective parameters to assess pain in cattle is substance P (SP), a neurotransmitter which is involved in the pain pathways. Research about SP concentration in calves focus on painful procedures, such as castration and dehorning. Basic research work is lacking; evaluation of SP concentrations in healthy calves and possible differences between sexes have not been published yet. The objectives of this study were to (1) describe SP concentrations in healthy male and female calves of the German Simmental breed to establish benchmarks of orientation, (2) compare SP concentrations between male and female calves, and (3) assess differences in SP concentrations between calves and adult cows. A total of 44 male and 49 female calves aged 14 to 21 days (17.1 ± 2.2 days) were included in this study. Blood samples were taken at 06:00 a.m. from the jugular vein, followed by a clinical examination. SP concentrations were analyzed using a commercial ELISA kit. Differences in SP concentrations according to laboratory parameters, and correlation of SP concentrations with different parameters were assessed. RESULTS Median SP concentrations in the blood plasma were 516 pg/ml (Interquartile Range 320 pg/ml, range 229-1615 pg/ml) in calves. Median SP concentrations differed significantly between male and female calves (554 pg/ml for male, and 489 pg/ml for female calves, respectively). There was no significant difference in animals with laboratory findings within reference ranges and those with mild deviations from reference ranges. There was a positive correlation between SP concentrations and leucocyte count, which was significant. SP concentrations were significantly lower in calves compared with a dataset of adult cows, which has been published previously. CONCLUSION Due to the high interindividual differences in SP concentrations, it is hard to establish benchmarks for orientation. Sex has a significant influence on SP concentrations. Research work should preferably be done in animals of the same sex. Also, animals should be within the same age range (adults or calves), as age seems to have an influence on SP concentrations.
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Affiliation(s)
- Anna Landinger
- Clinic for Ruminants with Ambulatory and Herd Health Services, Centre for Clinical Veterinary Medicine, LMU Munich, Sonnenstrasse 16, 85764, Oberschleissheim, Germany
| | - Yury Zablotski
- Clinic for Ruminants with Ambulatory and Herd Health Services, Centre for Clinical Veterinary Medicine, LMU Munich, Sonnenstrasse 16, 85764, Oberschleissheim, Germany
| | - Gabriela Knubben-Schweizer
- Clinic for Ruminants with Ambulatory and Herd Health Services, Centre for Clinical Veterinary Medicine, LMU Munich, Sonnenstrasse 16, 85764, Oberschleissheim, Germany
| | - Theresa Tschoner
- Clinic for Ruminants with Ambulatory and Herd Health Services, Centre for Clinical Veterinary Medicine, LMU Munich, Sonnenstrasse 16, 85764, Oberschleissheim, Germany.
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Landinger A, Zablotski Y, Knubben-Schweizer G, Tschoner T. Evaluation of Substance P concentrations in the blood plasma of jugular and tail vein of healthy German Simmental cows. BMC Vet Res 2023; 19:218. [PMID: 37864162 PMCID: PMC10588027 DOI: 10.1186/s12917-023-03768-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 10/03/2023] [Indexed: 10/22/2023] Open
Abstract
BACKGROUND Cattle strongly mask their pain, making the recognition and assessment of pain difficult. Different subjective and objective parameters to assess pain have been described. Substance P (SP), which is a neurotransmitter, is used to objectively evaluate nociception in cattle. However, SP concentrations have mainly been described in diseased animals, or animals subjected to painful procedures. To this day, no evaluation of SP in healthy adult cattle has been published. The objectives of this pilot study were to 1) assess the SP concentrations in healthy adult German Simmental cattle in the blood plasma, 2) compare the concentrations between the blood of the jugular and the tail vein, and 3) assess the concentrations in the blood of the tail vein every 6 h over a period of 24 h. A total of 52 healthy cattle of the German Simmental breed were included in this study. Animals were 5.0 ± 1.3 (mean ± SD) years old and between 117 and 239 (175.0 ± 34.1) days in milk. Blood samples were taken from the jugular vein (BJV, 07:45 a.m.) and the tail vein (TV1, 08:00 a.m.) each. Additional blood samples were taken every 6 h over the course of 24 h from the tail vein (TV2 - TV5). SP concentrations were analyzed using a commercial ELISA kit. RESULTS Mean (± SD) and median SP concentrations were 1.087 ± 436 pg/ml and 984 pg/ml for BJV (range 502 - 2,337 pg/ml), and 920 ± 402 pg/ml and 818 pg/ml for TV1 (range 192 - 2,531 pg/ml), respectively. There was a significantly positive correlation between SP concentrations of BJV and TV1. SP concentrations between BJV and TV1 were significantly different, as were SP concentrations in the tail vein between sampling times over the course of 24 h. CONCLUSIONS The results of this study show that blood samples to assess SP concentrations in cattle can be taken from the jugular as well as from the tail vein. There are high variations in concentrations between animals, and it is hard to define reference ranges for SP in healthy animals. Repeated blood samples should not be taken by repeated punctation of a vein but by use of a jugular vein catheter, which is a major limitation of the present study.
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Affiliation(s)
- Anna Landinger
- Clinic for Ruminants With Ambulatory and Herd Health Services at the Centre for Clinical Veterinary Medicine, LMU Munich, Sonnenstrasse 16, 85764, Oberschleissheim, Germany
| | - Yury Zablotski
- Clinic for Ruminants With Ambulatory and Herd Health Services at the Centre for Clinical Veterinary Medicine, LMU Munich, Sonnenstrasse 16, 85764, Oberschleissheim, Germany
| | - Gabriela Knubben-Schweizer
- Clinic for Ruminants With Ambulatory and Herd Health Services at the Centre for Clinical Veterinary Medicine, LMU Munich, Sonnenstrasse 16, 85764, Oberschleissheim, Germany
| | - Theresa Tschoner
- Clinic for Ruminants With Ambulatory and Herd Health Services at the Centre for Clinical Veterinary Medicine, LMU Munich, Sonnenstrasse 16, 85764, Oberschleissheim, Germany.
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Ivasiuk A, Matvieienko M, Kononenko NI, Duzhyy DE, Korogod SM, Voitenko N, Belan P. Diabetes-Induced Amplification of Nociceptive DRG Neuron Output by Upregulation of Somatic T-Type Ca 2+ Channels. Biomolecules 2023; 13:1320. [PMID: 37759720 PMCID: PMC10526307 DOI: 10.3390/biom13091320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/23/2023] [Accepted: 08/23/2023] [Indexed: 09/29/2023] Open
Abstract
The development of pain symptoms in peripheral diabetic neuropathy (PDN) is associated with the upregulation of T-type Ca2+ channels (T-channels) in the soma of nociceptive DRG neurons. Moreover, a block of these channels in DRG neurons effectively reversed mechanical and thermal hyperalgesia in animal diabetic models, indicating that T-channel functioning in these neurons is causally linked to PDN. However, no particular mechanisms relating the upregulation of T-channels in the soma of nociceptive DRG neurons to the pathological pain processing in PDN have been suggested. Here we have electrophysiologically identified voltage-gated currents expressed in nociceptive DRG neurons and developed a computation model of the neurons, including peripheral and central axons. Simulations showed substantially stronger sensitivity of neuronal excitability to diabetes-induced T-channel upregulation at the normal body temperature compared to the ambient one. We also found that upregulation of somatic T-channels, observed in these neurons under diabetic conditions, amplifies a single action potential invading the soma from the periphery into a burst of multiple action potentials further propagated to the end of the central axon. We have concluded that the somatic T-channel-dependent amplification of the peripheral nociceptive input to the spinal cord demonstrated in this work may underlie abnormal nociception at different stages of diabetes development.
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Affiliation(s)
- Arsentii Ivasiuk
- Department of Molecular Biophysics, Bogomoletz Institute of Physiology of NAS of Ukraine, 01024 Kyiv, Ukraine; (A.I.); (M.M.); (N.I.K.); (S.M.K.)
| | - Maksym Matvieienko
- Department of Molecular Biophysics, Bogomoletz Institute of Physiology of NAS of Ukraine, 01024 Kyiv, Ukraine; (A.I.); (M.M.); (N.I.K.); (S.M.K.)
| | - Nikolai I. Kononenko
- Department of Molecular Biophysics, Bogomoletz Institute of Physiology of NAS of Ukraine, 01024 Kyiv, Ukraine; (A.I.); (M.M.); (N.I.K.); (S.M.K.)
| | - Dmytro E. Duzhyy
- Department of Sensory Signaling, Bogomoletz Institute of Physiology of NAS of Ukraine, 01024 Kyiv, Ukraine;
| | - Sergiy M. Korogod
- Department of Molecular Biophysics, Bogomoletz Institute of Physiology of NAS of Ukraine, 01024 Kyiv, Ukraine; (A.I.); (M.M.); (N.I.K.); (S.M.K.)
| | - Nana Voitenko
- Department of Biomedicine and Neuroscience, Kyiv Academic University of NAS of Ukraine, 03142 Kyiv, Ukraine
- Research Center, Dobrobut Academy Medical School, 03022 Kyiv, Ukraine
| | - Pavel Belan
- Department of Molecular Biophysics, Bogomoletz Institute of Physiology of NAS of Ukraine, 01024 Kyiv, Ukraine; (A.I.); (M.M.); (N.I.K.); (S.M.K.)
- Department of Biomedicine and Neuroscience, Kyiv Academic University of NAS of Ukraine, 03142 Kyiv, Ukraine
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Wang Y, Huang R, Chai Z, Wang C, Du X, Hang Y, Xu Y, Li J, Jiang X, Wu X, Qiao Z, Li Y, Liu B, Zhang X, Cao P, Zhu F, Zhou Z. Ca 2+ -independent transmission at the central synapse formed between dorsal root ganglion and dorsal horn neurons. EMBO Rep 2022; 23:e54507. [PMID: 36148511 PMCID: PMC9638852 DOI: 10.15252/embr.202154507] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 08/07/2022] [Accepted: 08/30/2022] [Indexed: 09/25/2023] Open
Abstract
A central principle of synaptic transmission is that action potential-induced presynaptic neurotransmitter release occurs exclusively via Ca2+ -dependent secretion (CDS). The discovery and mechanistic investigations of Ca2+ -independent but voltage-dependent secretion (CiVDS) have demonstrated that the action potential per se is sufficient to trigger neurotransmission in the somata of primary sensory and sympathetic neurons in mammals. One key question remains, however, whether CiVDS contributes to central synaptic transmission. Here, we report, in the central transmission from presynaptic (dorsal root ganglion) to postsynaptic (spinal dorsal horn) neurons in vitro, (i) excitatory postsynaptic currents (EPSCs) are mediated by glutamate transmission through both CiVDS (up to 87%) and CDS; (ii) CiVDS-mediated EPSCs are independent of extracellular and intracellular Ca2+ ; (iii) CiVDS is faster than CDS in vesicle recycling with much less short-term depression; (iv) the fusion machinery of CiVDS includes Cav2.2 (voltage sensor) and SNARE (fusion pore). Together, an essential component of activity-induced EPSCs is mediated by CiVDS in a central synapse.
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Affiliation(s)
- Yuan Wang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Rong Huang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Zuying Chai
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Changhe Wang
- Department of NeurologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and TechnologyXi'an Jiaotong UniversityXi'anChina
| | - Xingyu Du
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Yuqi Hang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Yongxin Xu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Jie Li
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Xiaohan Jiang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Xi Wu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Zhongjun Qiao
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Yinglin Li
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Bing Liu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | | | - Peng Cao
- National Institute of Biological SciencesBeijingChina
| | - Feipeng Zhu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
| | - Zhuan Zhou
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular MedicineCollege of Future TechnologyPeking UniversityBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
- PKU‐IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina
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5
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Byun YS, Mok JW, Chung SH, Kim HS, Joo CK. Ocular surface inflammation induces de novo expression of substance P in the trigeminal primary afferents with large cell bodies. Sci Rep 2020; 10:15210. [PMID: 32939029 PMCID: PMC7494893 DOI: 10.1038/s41598-020-72295-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/26/2020] [Indexed: 01/05/2023] Open
Abstract
We evaluated the changes in substance P (SP)-expressing trigeminal neurons (TNs) innervating the cornea following ocular surface inflammation. Ocular surface inflammation was induced in Sprague-Dawley rats using 0.1% benzalkonium chloride (BAK). The corneal staining score, corneal epithelial apoptosis, conjunctival goblet cells, and density of corneal subbasal nerve plexus (SNP) were assessed, and the mRNA levels of SP, interleukin (IL)-1β, IL-6, and tumour necrosis factor-α were measured in corneas and ipsilateral trigeminal ganglia (TG). SP-immunoreactivity (IR) was measured in corneal intraepithelial nerves and TNs. The cell size of corneal TNs in the TG was calculated. All parameters were observed immediately (BAK group), at 1 week (1 w group), and 2 months (2 m group) after 2 weeks of BAK application. BAK caused an increase in the corneal staining score and the number of apoptotic cells, loss of conjunctival goblet cells, reduced density of corneal SNP, and upregulated expression of SP and inflammatory cytokines in both the cornea and TG in the BAK group but those changes were not observed in the 2 m group. On the other hand, SP-IR% and mean cell size of corneal TNs increased significantly in the BAK, 1 w, and 2 m groups, compared to the control. Our data suggest that following ocular surface inflammation, large-sized corneal TNs which normally do not express SP, expressed it and this phenotype switching lasted even after the inflammation disappeared. Long-lasting phenotypic switch, as well as changes in the expression level of certain molecules should be addressed in future studies on the mechanism of corneal neuropathic pain.
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Affiliation(s)
- Yong-Soo Byun
- Department of Ophthalmology and Visual Science, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Banpo-daero 222, Seocho-gu, Seoul, 06591, Republic of Korea.
- Catholic Institute of Visual Science, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Jee-Won Mok
- CK St. Mary's Eye Center, Seoul, Republic of Korea
| | - So-Hyang Chung
- Department of Ophthalmology and Visual Science, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Banpo-daero 222, Seocho-gu, Seoul, 06591, Republic of Korea
- Catholic Institute of Visual Science, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyun-Seung Kim
- Department of Ophthalmology and Visual Science, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Banpo-daero 222, Seocho-gu, Seoul, 06591, Republic of Korea
- Catholic Institute of Visual Science, The Catholic University of Korea, Seoul, Republic of Korea
| | - Choun-Ki Joo
- CK St. Mary's Eye Center, Seoul, Republic of Korea
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Chakrabarti S, Ai M, Henson FM, Smith ESJ. Peripheral mechanisms of arthritic pain: A proposal to leverage large animals for in vitro studies. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2020; 8:100051. [PMID: 32817908 PMCID: PMC7426561 DOI: 10.1016/j.ynpai.2020.100051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/22/2020] [Accepted: 07/22/2020] [Indexed: 04/14/2023]
Abstract
Pain arising from musculoskeletal disorders such as arthritis is one of the leading causes of disability. Whereas the past 20-years has seen an increase in targeted therapies for rheumatoid arthritis (RA), other arthritis conditions, especially osteoarthritis, remain poorly treated. Although modulation of central pain pathways occurs in chronic arthritis, multiple lines of evidence indicate that peripherally driven pain is important in arthritic pain. To understand the peripheral mechanisms of arthritic pain, various in vitro and in vivo models have been developed, largely in rodents. Although rodent models provide numerous advantages for studying arthritis pathogenesis and treatment, the anatomy and biomechanics of rodent joints differ considerably to those of humans. By contrast, the anatomy and biomechanics of joints in larger animals, such as dogs, show greater similarity to human joints and thus studying them can provide novel insight for arthritis research. The purpose of this article is firstly to review models of arthritis and behavioral outcomes commonly used in large animals. Secondly, we review the existing in vitro models and assays used to study arthritic pain, primarily in rodents, and discuss the potential for adopting these strategies, as well as likely limitations, in large animals. We believe that exploring peripheral mechanisms of arthritic pain in vitro in large animals has the potential to reduce the veterinary burden of arthritis in commonly afflicted species like dogs, as well as to improve translatability of pain research into the clinic.
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Affiliation(s)
- Sampurna Chakrabarti
- Department of Neuroscience, Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany
- Department of Pharmacology, University of Cambridge, UK
| | - Minji Ai
- Department of Veterinary Medicine, University of Cambridge, UK
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7
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Nencini S, Thai J, Ivanusic JJ. Sequestration of artemin reduces inflammation-induced activation and sensitization of bone marrow nociceptors in a rodent model of carrageenan-induced inflammatory bone pain. Eur J Pain 2018; 23:397-409. [PMID: 30218545 DOI: 10.1002/ejp.1315] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/15/2018] [Accepted: 09/04/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Pathologies that affect the bone marrow have a significant inflammatory component; however, it is not clear how inflammatory mediators affect nociceptive nerve terminals within the marrow cavity. METHODS In this study, an in vivo bone-nerve preparation was used to directly record the physiological response properties of bone marrow nociceptors innervating the tibial marrow cavity of rats, before and after application of the inflammatory agent carrageenan. In addition, endogenous artemin was sequestered by application of an artemin neutralizing antibody to determine if this could prevent the inflammation-induced physiological changes observed. RESULTS A single injection of carrageenan administered into the tibial marrow cavity produced rapid changes in weight bearing (pain-like behaviour) in conscious animals. Carrageenan, but not saline, activated bone marrow nociceptors in whole-nerve recordings and sensitized a subtype of Aδ-bone marrow nociceptors to mechanical stimulation. The activation and sensitization had a rapid time course that matched that of pain-like behaviours. Sequestration of endogenous artemin significantly reduced carrageenan-induced increases in ongoing activity and completely abolished sensitization of bone marrow nociceptors to mechanical stimulation. CONCLUSIONS These observations indicate that inflammation affects the activity and sensitivity of bone marrow nociceptors; that artemin plays a role in these changes; and that artemin might be a promising target for pharmacological manipulations in the treatment of inflammatory bone pain. SIGNIFICANCE Most pathologies that affect the bone marrow have an inflammatory component. We have used a model of carrageenan-induced inflammation to show that sequestration of artemin reduces inflammation-induced activation and sensitization of bone marrow nociceptors. Our findings suggest that artemin signalling is a target for the treatment of inflammatory bone pain.
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Affiliation(s)
- Sara Nencini
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | - Jenny Thai
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | - Jason J Ivanusic
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
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8
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Rat model of cancer-induced bone pain: changes in nonnociceptive sensory neurons in vivo. Pain Rep 2017; 2:e603. [PMID: 29392218 PMCID: PMC5741358 DOI: 10.1097/pr9.0000000000000603] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 04/15/2017] [Accepted: 04/25/2017] [Indexed: 01/31/2023] Open
Abstract
Nonnociceptive sensory neurons relate to transient episodes of intense pain that characterize neuropathic pain. They are involved in the peripheral sensitization and tactile hypersensitivity. Introduction: Clinical data on cancer-induced bone pain (CIBP) suggest extensive changes in sensory function. In a previous investigation of an animal model of CIBP, we have observed that changes in intrinsic membrane properties and excitability of dorsal root ganglion (DRG) nociceptive neurons correspond to mechanical allodynia and hyperalgesia. Objectives: To investigate the mechanisms underlying changes in nonnociceptive sensory neurons in this model, we have compared the electrophysiological properties of primary nonnociceptive sensory neurons at <1 and >2 weeks after CIBP model induction with properties in sham control animals. Methods: Copenhagen rats were injected with 106 MAT-LyLu rat prostate cancer cells into the distal femur epiphysis to generate a model of CIBP. After von Frey tactile measurement of mechanical withdrawal thresholds, the animals were prepared for acute electrophysiological recordings of mechanically sensitive neurons in the DRG in vivo. Results: The mechanical withdrawal threshold progressively decreased in CIBP model rats. At <1 week after model induction, there were no changes observed in nonnociceptive Aβ-fiber DRG neurons between CIBP model rats and sham rats. However, at >2 weeks, the Aβ-fiber low-threshold mechanoreceptors (LTMs) in CIBP model rats exhibited a slowing of the dynamics of action potential (AP) genesis, including wider AP duration and lower AP amplitude compared with sham rats. Furthermore, enhanced excitability of Aβ-fiber LTM neurons was observed as an excitatory discharge in response to intracellular injection of depolarizing current into the soma. Conclusion: After induction of the CIBP model, Aβ-fiber LTMs at >2 weeks but not <1 week had undergone changes in electrophysiological properties. Importantly, changes observed are consistent with observations in models of peripheral neuropathy. Thus, Aβ-fiber nonnociceptive primary sensory neurons might be involved in the peripheral sensitization and tumor-induced tactile hypersensitivity in CIBP.
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9
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Smith-Edwards KM, DeBerry JJ, Saloman JL, Davis BM, Woodbury CJ. Profound alteration in cutaneous primary afferent activity produced by inflammatory mediators. eLife 2016; 5. [PMID: 27805567 PMCID: PMC5117853 DOI: 10.7554/elife.20527] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 11/01/2016] [Indexed: 12/13/2022] Open
Abstract
Inflammatory pain is thought to arise from increased transmission from nociceptors and recruitment of 'silent' afferents. To evaluate inflammation-induced changes, mice expressing GCaMP3 in cutaneous sensory neurons were generated and neuronal responses to mechanical stimulation in vivo before and after subcutaneous infusion of an 'inflammatory soup' (IS) were imaged in an unanesthetized preparation. Infusion of IS rapidly altered mechanical responsiveness in the majority of neurons. Surprisingly, more cells lost, rather than gained, sensitivity and 'silent' afferents that were mechanically insensitive and gained mechanosensitivity after IS exposure were rare. However, the number of formerly 'silent' afferents that became mechanosensitive was increased five fold when the skin was heated briefly prior to infusion of IS. These findings suggest that pain arising from inflamed skin reflects a dramatic shift in the balance of sensory input, where gains and losses in neuronal populations results in novel output that is ultimately interpreted by the CNS as pain.
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Affiliation(s)
- Kristen M Smith-Edwards
- Department of Zoology and Physiology, University of Wyoming, Laramie, United States.,University of Wyoming Graduate Program in Neuroscience, Laramie, United States
| | - Jennifer J DeBerry
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States.,Center for Neuroscience at the University of Pittsburgh, Pittsburgh, United States.,Pittsburgh Center for Pain Research, Pittsburgh, United States
| | - Jami L Saloman
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States.,Center for Neuroscience at the University of Pittsburgh, Pittsburgh, United States.,Pittsburgh Center for Pain Research, Pittsburgh, United States
| | - Brian M Davis
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States.,Center for Neuroscience at the University of Pittsburgh, Pittsburgh, United States.,Pittsburgh Center for Pain Research, Pittsburgh, United States
| | - C Jeffery Woodbury
- Department of Zoology and Physiology, University of Wyoming, Laramie, United States
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10
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Remote dose-dependent effects of dry needling at distant myofascial trigger spots of rabbit skeletal muscles on reduction of substance P levels of proximal muscle and spinal cords. BIOMED RESEARCH INTERNATIONAL 2014; 2014:982121. [PMID: 25276839 PMCID: PMC4168154 DOI: 10.1155/2014/982121] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 08/15/2014] [Indexed: 11/28/2022]
Abstract
Background. Dry needling at distant myofascial trigger points is an effective pain management in patients with myofascial pain. However, the biochemical effects of remote dry needling are not well understood. This study evaluates the remote effects of dry needling with different dosages on the expressions of substance P (SP) in the proximal muscle, spinal dorsal horns of rabbits. Methods. Male New Zealand rabbits (2.5–3.0 kg) received dry needling at myofascial trigger spots of a gastrocnemius (distant muscle) in one (1D) or five sessions (5D). Bilateral biceps femoris (proximal muscles) and superficial laminaes of L5-S2, T2-T5, and C2-C5 were sampled immediately and 5 days after dry needling to determine the levels of SP using immunohistochemistry and western blot. Results. Immediately after dry needling for 1D and 5D, the expressions of SP were significantly decreased in ipsilateral biceps femoris and bilateral spinal superficial laminaes (P < .05). Five days after dry needling, these reduced immunoactivities of SP were found only in animals receiving 5D dry needling (P < .05). Conclusions. This remote effect of dry needling involves the reduction of SP levels in proximal muscle and spinal superficial laminaes, which may be closely associated with the control of myofascial pain.
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Bishop T, Ballard A, Holmes H, Young AR, McMahon SB. Ultraviolet-B induced inflammation of human skin: Characterisation and comparison with traditional models of hyperlagesia. Eur J Pain 2012; 13:524-32. [DOI: 10.1016/j.ejpain.2008.06.006] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2008] [Revised: 05/27/2008] [Accepted: 06/07/2008] [Indexed: 10/21/2022]
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Nakajima A, Tsuboi Y, Suzuki I, Honda K, Shinoda M, Kondo M, Matsuura S, Shibuta K, Yasuda M, Shimizu N, Iwata K. PKCgamma in Vc and C1/C2 is involved in trigeminal neuropathic pain. J Dent Res 2011; 90:777-81. [PMID: 21393551 DOI: 10.1177/0022034511401406] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The aim of the present study was to clarify the involvement of protein kinase Cγ (PKCγ) in the facial neuropathic pain following infraorbital nerve injury. We analyzed the change in PKCγ expression in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1/C2) following chronic constriction injury of the infraorbital nerve (ION-CCI). We also studied ION-CCI-mediated mechanical nocifensive behavior in rats. The mechanical head-withdrawal threshold significantly decreased 1 to 14 days after ION-CCI compared with that before ION-CCI and in sham rats. The expression of PKCγ was significantly larger in the ipsilateral Vc compared with the contralateral side in ION-CCI rats 3, 7, and 14 days after ION-CCI. Intrathecal (i.t.) administration of the PKCγ inhibitor chelerythrine prevented an increase in the PKCγ expression in the ipsilateral Vc. Moreover, i.t. administration of chelerythrine annulled ION-CCI-mediated reduction in the head-withdrawal threshold. Taken together, these findings suggest that PKCγ expression in the Vc played an important role in the mechanism of orofacial static mechanical allodynia following trigeminal nerve injury.
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Affiliation(s)
- A Nakajima
- Department of Orthodontics, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan
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13
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Wu Q, Henry JL. Changes in Abeta non-nociceptive primary sensory neurons in a rat model of osteoarthritis pain. Mol Pain 2010; 6:37. [PMID: 20594346 PMCID: PMC2908067 DOI: 10.1186/1744-8069-6-37] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Accepted: 07/01/2010] [Indexed: 11/18/2022] Open
Abstract
Background Pain is a major debilitating factor in osteoarthritis (OA), yet few mechanism-based therapies are available. To address the need to understand underlying mechanisms the aim of the present study was to determine changes in sensory neurons in an animal model of OA pain. Results The model displayed typical osteoarthritis pathology characterized by cartilage degeneration in the knee joint and also manifested knee pathophysiology (edema and increased vasculature permeability of the joint) and altered nociception of the affected limb (hind paw tenderness and knee articulation-evoked reduction in the tail flick latency). Neurons included in this report innervated regions throughout the entire hind limb. Aβ-fiber low threshold mechanoreceptors exhibited a slowing of the dynamics of action potential (AP) genesis, including wider AP duration and slower maximum rising rate, and muscle spindle neurons were the most affected subgroup. Only minor AP configuration changes were observed in either C- or Aδ-fiber nociceptors. Conclusion Thus, at one month after induction of the OA model Aβ-fiber low threshold mechanoreceptors but not C- or Aδ-fiber nociceptors had undergone changes in electrophysiological properties. If these changes reflect a change in functional role of these neurons in primary afferent sensory processing, then Aβ-fiber non-nociceptive primary sensory neurons may be involved in the pathogenesis of OA pain. Further, it is important to point out that the patterns of the changes we observed are consistent with observations in models of peripheral neuropathy but not models of peripheral inflammation.
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Affiliation(s)
- Qi Wu
- Psychiatry and Behavioral Neurosciences, McMaster University, HSC 4N35, Hamilton, Ontario, Canada
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14
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Pain research in China. SCIENCE CHINA-LIFE SCIENCES 2010; 53:356-362. [DOI: 10.1007/s11427-010-0065-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Accepted: 02/24/2010] [Indexed: 12/29/2022]
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15
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Zheng H, Fan J, Xiong W, Zhang C, Wang XB, Liu T, Liu HJ, Sun L, Wang YS, Zheng LH, Wang BR, Zhang CX, Zhou Z. Action potential modulates Ca2+-dependent and Ca2+-independent secretion in a sensory neuron. Biophys J 2009; 96:2449-56. [PMID: 19289069 DOI: 10.1016/j.bpj.2008.11.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2008] [Accepted: 11/17/2008] [Indexed: 11/28/2022] Open
Abstract
Neurotransmitter release normally requires calcium triggering. However, the somata of dorsal root ganglion (DRG) neurons possess a calcium-independent but voltage-dependent secretion (CIVDS) in addition to the classic calcium-dependent secretion (CDS). Here, we investigated the physiological role of CIVDS and the contributions of CIVDS and CDS induced by action potentials (APs) in DRG soma. Using membrane capacitance measurements, caged calcium photolysis, and membrane capacitance kinetics analysis, we demonstrated that AP-induced secretion had both CIVDS and CDS components. Following physiological stimuli, the dominant component of AP-induced secretion was either CIVDS for spontaneous firing or CDS for high-intensity stimuli. AP frequency modulates CDS-coupled exocytosis and CIVDS-coupled endocytosis but not CIVDS-coupled exocytosis and CDS-coupled endocytosis. Finally, CIVDS did not contribute to excitatory postsynaptic currents induced by APs in DRG presynaptic terminals in the spinal cord. Thus, CIVDS is probably an essential physiological component of AP-induced secretion in the soma. These findings bring novel insights into primary sensory processes in DRG neurons.
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Affiliation(s)
- Hui Zheng
- Institute of Molecular Medicine, Peking University, Beijing, China
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16
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Zhao ZQ. Neural mechanism underlying acupuncture analgesia. Prog Neurobiol 2008; 85:355-75. [PMID: 18582529 DOI: 10.1016/j.pneurobio.2008.05.004] [Citation(s) in RCA: 722] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2007] [Revised: 03/19/2008] [Accepted: 05/30/2008] [Indexed: 12/16/2022]
Abstract
Acupuncture has been accepted to effectively treat chronic pain by inserting needles into the specific "acupuncture points" (acupoints) on the patient's body. During the last decades, our understanding of how the brain processes acupuncture analgesia has undergone considerable development. Acupuncture analgesia is manifested only when the intricate feeling (soreness, numbness, heaviness and distension) of acupuncture in patients occurs following acupuncture manipulation. Manual acupuncture (MA) is the insertion of an acupuncture needle into acupoint followed by the twisting of the needle up and down by hand. In MA, all types of afferent fibers (Abeta, Adelta and C) are activated. In electrical acupuncture (EA), a stimulating current via the inserted needle is delivered to acupoints. Electrical current intense enough to excite Abeta- and part of Adelta-fibers can induce an analgesic effect. Acupuncture signals ascend mainly through the spinal ventrolateral funiculus to the brain. Many brain nuclei composing a complicated network are involved in processing acupuncture analgesia, including the nucleus raphe magnus (NRM), periaqueductal grey (PAG), locus coeruleus, arcuate nucleus (Arc), preoptic area, nucleus submedius, habenular nucleus, accumbens nucleus, caudate nucleus, septal area, amygdale, etc. Acupuncture analgesia is essentially a manifestation of integrative processes at different levels in the CNS between afferent impulses from pain regions and impulses from acupoints. In the last decade, profound studies on neural mechanisms underlying acupuncture analgesia predominately focus on cellular and molecular substrate and functional brain imaging and have developed rapidly. Diverse signal molecules contribute to mediating acupuncture analgesia, such as opioid peptides (mu-, delta- and kappa-receptors), glutamate (NMDA and AMPA/KA receptors), 5-hydroxytryptamine, and cholecystokinin octapeptide. Among these, the opioid peptides and their receptors in Arc-PAG-NRM-spinal dorsal horn pathway play a pivotal role in mediating acupuncture analgesia. The release of opioid peptides evoked by electroacupuncture is frequency-dependent. EA at 2 and 100Hz produces release of enkephalin and dynorphin in the spinal cord, respectively. CCK-8 antagonizes acupuncture analgesia. The individual differences of acupuncture analgesia are associated with inherited genetic factors and the density of CCK receptors. The brain regions associated with acupuncture analgesia identified in animal experiments were confirmed and further explored in the human brain by means of functional imaging. EA analgesia is likely associated with its counter-regulation to spinal glial activation. PTX-sesntive Gi/o protein- and MAP kinase-mediated signal pathways as well as the downstream events NF-kappaB, c-fos and c-jun play important roles in EA analgesia.
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Affiliation(s)
- Zhi-Qi Zhao
- Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
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18
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Ma C, LaMotte RH. Multiple sites for generation of ectopic spontaneous activity in neurons of the chronically compressed dorsal root ganglion. J Neurosci 2007; 27:14059-68. [PMID: 18094245 PMCID: PMC3035427 DOI: 10.1523/jneurosci.3699-07.2007] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Revised: 10/22/2007] [Accepted: 11/12/2007] [Indexed: 01/15/2023] Open
Abstract
In a chronically compressed dorsal root ganglion (CCD) in the rat, a model of foraminal stenosis and radicular pain in human, a subpopulation of neurons with functional axons exhibits spontaneous activity (SA) that originates within the ganglion. Intracellular electrophysiological recordings were obtained from the somata of neurons of the compressed ganglion both in vitro and in vivo. The SA was classified into two types according to the presence (type I) or absence (type II) of subthreshold membrane potential oscillation. Neurons with type I SA had significantly higher somal excitability than those with type II SA. In most cases, depolarization of the membrane potential by current injection increased the discharge rates of type I--but not type II SA. Both types occasionally coexisted in the same neuron. Several lines of evidence suggested that the origin of SA in the DRG was most likely the soma for type I SA and the axon for type II. Therefore CCD neurons have multiple sites for generation of action potentials other than the terminal endings. In vivo recordings revealed the same two types of SA in a subpopulation of neurons with functionally characterized peripheral receptive fields. Thus, SA might not only produce spurious sensory input to the afferent pathways but also add to or block impulse transmission generated by natural stimulation of peripheral receptors. SA originating in the compressed ganglion is likely to interfere with sensory transmission in nociceptive and non-nociceptive neurons, thereby contributing to radicular pain, paresthesias, hyperalgesia and allodynia.
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Affiliation(s)
- Chao Ma
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Robert H. LaMotte
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut 06510
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Abstract
The investigative evidence and emerging concepts in neurogastroenterology implicate dysfunctions at the levels of the enteric and central nervous systems as underlying causes of the prominent symptoms of many of the functional gastrointestinal disorders. Neurogastroenterological research aims for improved understanding of the physiology and pathophysiology of the digestive subsystems from which the arrays of functional symptoms emerge. The key subsystems for defecation-related symptoms and visceral hyper-sensitivity are the intestinal secretory glands, the musculature and the nervous system that controls and integrates their activity. Abdominal pain and discomfort arising from these systems adds the dimension of sensory neurophysiology. This review details current concepts for the underlying pathophysiology in terms of the physiology of intestinal secretion, motility, nervous control, sensing function, immuno-neural communication and the brain-gut axis.
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Zheng JH, Walters ET, Song XJ. Dissociation of dorsal root ganglion neurons induces hyperexcitability that is maintained by increased responsiveness to cAMP and cGMP. J Neurophysiol 2006; 97:15-25. [PMID: 17021029 DOI: 10.1152/jn.00559.2006] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Injury or inflammation affecting sensory neurons in dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spontaneous firing and neuropathic pain. Recent results indicate that after chronic compression of DRG (CCD treatment), both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by concurrent activity in cAMP-protein kinase A (PKA) and cGMP-protein kinase G (PKG) signaling pathways. We report here that when tested under identical conditions, dissociation produces a pattern of hyperexcitability in small DRG neurons similar to that produced by CCD treatment, manifest as decreased action potential (AP) current threshold, increased AP duration, increased repetitive firing to depolarizing pulses, increased spontaneous firing and resting depolarization. A novel feature of this hyperexcitability is its early expression-as soon as testing can be conducted after dissociation (approximately 2 h). Both forms of injury increase the electrophysiological responsiveness of the neurons to activation of cAMP-PKA and cGMP-PKG pathways as indicated by enhancement of hyperexcitability by agonists of these pathways in dissociated or CCD-treated neurons but not in control neurons. Although inflammatory signals are known to activate cAMP-PKA pathways, dissociation-induced hyperexcitability is unlikely to be triggered by signals released from inflammatory cells recruited to the DRG because of insufficient time for recruitment during the dissociation procedure. Inhibition by specific antagonists indicates that continuing activation of cAMP-PKA and cGMP-PKG pathways is required to maintain hyperexcitability after dissociation. The reduction of hyperexcitability by blockers of adenylyl cyclase and soluble guanylyl cyclase after dissociation suggests a continuing release of autocrine and/or paracrine factors from dissociated neurons and/or satellite cells, which activate both cyclases and help to maintain acute, injury-induced hyperexcitability of DRG neurons.
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Affiliation(s)
- Ji-Hong Zheng
- Department of Neurobiology, Parker College Research Institute, 2500 Walnut Hill Lane, Dallas, TX 75229, USA.
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Alessandri-Haber N, Dina OA, Joseph EK, Reichling D, Levine JD. A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators. J Neurosci 2006; 26:3864-74. [PMID: 16597741 PMCID: PMC6674137 DOI: 10.1523/jneurosci.5385-05.2006] [Citation(s) in RCA: 170] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The transient receptor potential vanilloid 4 (TRPV4) is a primary afferent transducer that plays a crucial role in neuropathic hyperalgesia for osmotic and mechanical stimuli, as well as in inflammatory mediator-induced hyperalgesia for osmotic stimuli. In view of the clinical importance of mechanical hyperalgesia in inflammatory states, the present study investigated the role of TRPV4 in mechanical hyperalgesia induced by inflammatory mediators and the second-messenger pathways involved. Intradermal injection of either the inflammogen carrageenan or a soup of inflammatory mediators enhanced the nocifensive paw-withdrawal reflex elicited by hypotonic or mechanical stimuli in rat. Spinal administration of TRPV4 antisense oligodeoxynucleotide blocked the enhancement without altering baseline nociceptive threshold. Similarly, in TRPV4(-/-) knock-out mice, inflammatory soup failed to induce any significant mechanical or osmotic hyperalgesia. In vitro investigation showed that inflammatory mediators engage the TRPV4-mediated mechanism of sensitization by direct action on dissociated primary afferent neurons. Additional behavioral observations suggested that multiple mediators are necessary to achieve sufficient activation of the cAMP pathway to engage the TRPV4-dependent mechanism of hyperalgesia. In addition, direct activation of protein kinase A or protein kinase C epsilon, two pathways that mediate inflammation-induced mechanical hyperalgesia, also induced hyperalgesia for both hypotonic and mechanical stimuli that was decreased by TRPV4 antisense and absent in TRPV4(-/-) mice. We conclude that TRPV4 plays a crucial role in the mechanical hyperalgesia that is generated by the concerted action of inflammatory mediators present in inflamed tissues.
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Affiliation(s)
- Nicole Alessandri-Haber
- Division of Neurosciences, Department of Oral and Maxillofacial Surgery, University of California, San Francisco, California 94143-0440, USA.
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22
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Aita M, Maeda T, Takagi R, Seo K. Postnatal development of substance P-immunoreaction in the trigeminal caudalis of neonatally capsaicin-treated mice. ACTA ACUST UNITED AC 2006; 68:311-20. [PMID: 16477150 DOI: 10.1679/aohc.68.311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The trigeminal subnucleus caudalis (Vc) is a critical relay site for processing nociceptive afferent input from the orofacial area in addition to its modulation by neuroplastic change. Although an administration of capsaicin in neonates induces a selective destruction of substance P (SP)-immunoreactive nerve fibers, little information is available regarding its detailed effects on the Vc, particularly during postnatal development. The present study examined postnatal changes in the distribution of SP in the Vc and trigeminal ganglion (TG) by immunohistochemical techniques in naïve (NV) and neonatally capsaicin-treated (CP) mice, combined with a quantitative analysis. The neonatal mice received a single subcutaneous injection of capsaicin (50 mg/kg) at 48 hours after birth. The neural density of the SP-immunoreaction decreased to approximately a quarter of that in 1-week-old NV mice but increased to three-quarters of that in the NV in the superficial area after postnatal week 2. A double staining with SP and myelin basic protein confirmed the absence of any SP-immunoreaction in the myelinated nerve fibers in both NV and CP mice. The SP-immunoreaction never overlapped with non-peptidergic IB4-labeled neurons in the Vc and TG of either group. Neither the size distribution of SP-positive neurons nor their relative ratio in the TG differed between NV and CP mice at the ages of postnatal weeks 1 and 8. These findings indicate two putative origins for the emergent SP-immunoreaction in the superficial layer of the Vc of the CP mice: the surviving trigeminal neurons with SP against capsaicin treatment and/or intrinsic neurons/interneurons in the Vc without SP under normal conditions.
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Affiliation(s)
- Megumi Aita
- Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Japan
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Fang X, McMullan S, Lawson SN, Djouhri L. Electrophysiological differences between nociceptive and non-nociceptive dorsal root ganglion neurones in the rat in vivo. J Physiol 2005; 565:927-43. [PMID: 15831536 PMCID: PMC1464557 DOI: 10.1113/jphysiol.2005.086199] [Citation(s) in RCA: 176] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/05/2005] [Accepted: 04/13/2005] [Indexed: 12/31/2022] Open
Abstract
Intracellular recordings were made from 1022 somatic lumbar dorsal root ganglion (DRG) neurones in anaesthetized adult rats, classified from dorsal root conduction velocities (CVs) as C, Adelta or Aalpha/beta, and according to their responses to mechanical and thermal stimuli as nociceptive (including high-threshold mechanoreceptive (HTM) units), and non-nociceptive (including low-threshold mechanoreceptive (LTM) and cooling units). Of these, 463 met electrophysiological criteria for analysis of action potentials (APs) evoked by dorsal root stimulation. These included 47 C-, 71 Adelta- and 102 Aalpha/beta-nociceptive, 10 C-, 8 Adelta- and 178 Aalpha/beta-LTM, 18 C- and 19 Adelta- unresponsive, and 4 C-cooling units. Medians of AP and afterhyperpolarization (AHP) durations and AP overshoots were significantly greater for nociceptive than LTM units in all CV groups. AP overshoots and AHP durations were similar in nociceptors of all CV groups whereas AP durations were greater in slowly conducting, especially C-fibre, nociceptors. C-cooling units had faster CVs, smaller AP overshoots and shorter AP durations than C-HTM units. A subgroup of Aalpha/beta-HTM, moderate pressure units, had faster CVs and AP kinetics than other Aalpha/beta-HTM units. Of the Aalpha/beta-LTM units, muscle spindle afferents had the fastest CV and AP kinetics, while rapidly adapting cutaneous units had the slowest AP kinetics. AP variables in unresponsive and nociceptive units were similar in both C- and Adelta-fibre CV groups. The ability of fibres to follow rapid stimulus trains (fibre maximum following frequency) was correlated with CV but not sensory modality. These findings indicate both the usefulness and limitations of using electrophysiological criteria for identifying neurones acutely in vitro as nociceptive.
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Affiliation(s)
- X Fang
- Department of Physiology, University of Bristol, Medical School, University Walk, Bristol BS8 1TD, UK
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Ma C, LaMotte RH. Enhanced excitability of dissociated primary sensory neurons after chronic compression of the dorsal root ganglion in the rat. Pain 2005; 113:106-12. [PMID: 15621370 DOI: 10.1016/j.pain.2004.10.001] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2004] [Revised: 09/15/2004] [Accepted: 09/28/2004] [Indexed: 11/29/2022]
Abstract
A chronic compression of the dorsal root ganglion (CCD) produces ipsilateral cutaneous hyperalgesia and allodynia in rats. Intracellular electrophysiological recordings from formerly compressed neurons in the intact dorsal root ganglion (DRG) reveal lower than normal current thresholds (CTs) and abnormal spontaneous activity (SA) (Zhang JM, Song XJ, LaMotte RH. Enhanced excitability of sensory neurons in rats with cutaneous hyperalgesia produced by chronic compression of the dorsal root ganglion. J Neurophysiol 1999;82:3359-66). To determine if the neuronal hyperexcitability is intrinsic to the soma, L4 and L5 DRG neurons from rats that had prior CCD surgery or those that did not (controls) were dissociated, and intracellular recordings obtained 3-8 h (acute) or 24-30 h (1d) after culture. The CTs of large- (>45 microm diameter) and medium- (30 approximately 45 microm) sized neurons from control rats after acute or 1d culture were similar to those formerly recorded from the intact DRG and significantly lower for CCD than for control rats. However, the CTs of small- (<or=30 microm) sized neurons from control rats were significantly lower in acute or 1d culture groups than they were in the intact DRG and not significantly different from those of dissociated small neurons from CCD rats. The overall incidence of SA was higher for CCD than for control neurons after 1d culture (10.3 vs. 1.8%) and similar to that obtained in the intact DRG. We conclude that the CCD-induced hyperexcitability of medium- and large-sized neurons remains after dissociation and is intrinsic to the soma. For small-sized neurons, the effects of CCD observed in the intact DRG are less apparent after dissociation possibly due to the hyperexcitability produced by the dissociation process itself.
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Affiliation(s)
- Chao Ma
- Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510, USA
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Affiliation(s)
- Darryl L Millis
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, USA
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Li S, Zhao ZQ. Morphine-induced decrease in mechanical allodynia is mediated by central, but not peripheral, opioid receptors in rats with inflammation. Eur J Pharmacol 2004; 481:203-6. [PMID: 14642787 DOI: 10.1016/j.ejphar.2003.09.032] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The aim of this study was to investigate the mechanism underlying the effect of morphine on allodynia to complete Freund's adjuvant-induced inflammation in rats. Morphine (5 mg/kg, i.v.) markedly inhibited the mechanical stimulation-induced nociceptive reflex of the gastrocnemius muscle in the inflamed hind-limb, and the inhibition was blocked by naloxone (1 mg/kg). Teased fiber recordings were made from the tibial nerve innervating the inflamed hindpaw. Morphine at the same dose did not affect the spontaneous firing rate of A-type fibers, whereas it markedly decreased the spontaneous firing of C-type fibers. The present data suggested that the central, but not peripheral, plasticity triggered by inflammation-induced facilitation of A(beta) fibers plays an important role in morphine-induced alleviation of allodynia, whereas activation of opioid receptor expression on the peripheral terminals of C fibers may contribute to morphine-induced alleviation of persistent pain of inflammation.
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Affiliation(s)
- Shao Li
- Institute of Neurobiology, Fudan University, Shanghai 200433, China
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Koppert W, Brueckl V, Weidner C, Schmelz M. Mechanically induced axon reflex and hyperalgesia in human UV-B burn are reduced by systemic lidocaine. Eur J Pain 2004; 8:237-44. [PMID: 15109974 DOI: 10.1016/j.ejpain.2003.08.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2002] [Accepted: 08/28/2003] [Indexed: 11/30/2022]
Abstract
The mechanisms for the induction of primary mechanical hyperalgesia are unclear. We analyzed the neurogenic axon reflex erythema (flare) following phasic mechanical stimulation in normal and in UV-B irradiated skin. In a cross-over double blind design (n = 10), low dose of systemic lidocaine suppressed mechanical hyperalgesia in sunburned skin and in the mechanically induced flare. Phasic mechanical stimulation, even at painful intensities, did not evoke a flare reaction in normal skin. However, stimulation within the UV-B burn dose-dependently provoked an immediate flare reaction. Systemic lidocaine suppressed the mechanically induced flare as well as the mechanical hyperalgesia in sunburned skin, while leaving the impact-induced ratings in normal skin unchanged. Systemic lidocaine reduced these effects of sensitization, but did not reduce ratings in normal skin. As mechanically insensitive ("sleeping") nociceptors have been shown to mediate the axon-reflex in human skin, sensitization of this class of nociceptors might contribute also to the UV-B-induced primary mechanical hyperalgesia.
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Kelly S, Chapman V. Cannabinoid CB1 receptor inhibition of mechanically evoked responses of spinal neurones in control rats, but not in rats with hindpaw inflammation. Eur J Pharmacol 2003; 474:209-16. [PMID: 12921864 DOI: 10.1016/s0014-2999(03)02085-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Spinally administered cannabinoid receptor agonists are anti-nociceptive in a variety of models of acute and persistent pain. The present study investigated the effects of activation of spinal cannabinoid CB(1) receptors on mechanically evoked responses of spinal neurones in acute and inflammatory pain states. In vivo electrophysiology studies were carried out in anaesthetised rats. Effects of spinal administration of a selective cannabinoid CB(1) receptor agonist, arachidonyl-2-chloroethylamide (ACEA), on mechanically evoked responses of dorsal horn neurones in control rats and rats with peripheral hindpaw carrageenan-induced inflammation were compared. ACEA (0.27 nM-27 microM) significantly inhibited innocuous and noxious mechanically evoked responses of dorsal horn neurones in control rats. Pre-administration of the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxyamide, SR141716A, (0.43 microM) attenuated the inhibitory effects of ACEA (27 microM). ACEA did not alter mechanically evoked responses of dorsal horn neurones in rats with hindpaw carrageenan-induced inflammation. Following peripheral inflammation, there is a loss of spinal CB(1) receptor-mediated inhibition of mechanically evoked responses, which is suggestive of a functional down-regulation of CB(1) receptors under these conditions.
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MESH Headings
- Animals
- Arachidonic Acids/pharmacology
- Dose-Response Relationship, Drug
- Evoked Potentials/drug effects
- Evoked Potentials/physiology
- Hindlimb/drug effects
- Hindlimb/metabolism
- Inflammation/chemically induced
- Inflammation/metabolism
- Male
- Nerve Fibers, Unmyelinated/drug effects
- Nerve Fibers, Unmyelinated/physiology
- Neural Inhibition/drug effects
- Neural Inhibition/physiology
- Pain Measurement/drug effects
- Pain Measurement/methods
- Physical Stimulation/methods
- Posterior Horn Cells/drug effects
- Posterior Horn Cells/metabolism
- Rats
- Rats, Sprague-Dawley
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB1/metabolism
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Affiliation(s)
- Sara Kelly
- University of Nottingham Medical School, Queen's Medical Centre, NG7 2UH Nottingham, UK
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29
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Xu GY, Zhao ZQ. Cross-inhibition of mechanoreceptive inputs in dorsal root ganglia of peripheral inflammatory cats. Brain Res 2003; 970:188-94. [PMID: 12706260 DOI: 10.1016/s0006-8993(03)02342-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Primary afferent neurons in mammalian dorsal root ganglia (DRGs) normally function as independent sensory communication elements. However, it has recently been shown that most DRG neurons are transiently activated when axons of neighboring neurons of the same ganglion are stimulated repetitively and the cross-depolarization contributes to this mutual cross-excitation. Here, we reported the cross-inhibition of mechanoreceptive information in DRG under peripheral inflammatory condition. Intracellular recordings were made in vivo from A-type afferent neurons in cat L(6-7) DRGs. Among spontaneously firing neurons both from control (Con) and carrageenan (Carg) injected cats, some A-type afferent neurons showed to have two distinct receptive fields on the hindpaw. Mechanical stimulation of one receptive field increased the ongoing activities, while stimulation of the other receptive field led to a decrease of spontaneous firings of the same neuron. These two distinct receptive fields are termed excitatory receptive field (ERF) and inhibitory receptive field (IRF), respectively. Peripheral inflammation significantly increased the prevalence of Abeta and Adelta neurons with two distinct receptive fields (Abeta: Con, 1.34%, n=149; Carg, 6.59%, n=182; P<0.05; Adelta: Con, 0%, n=138, Carg, 3.9%, n=102, P<0.05). Most interestedly, ERF stimulation-induced enhancement of cell firings can be suppressed by IRF stimulation. Similarly, IRF stimulation-induced decrease of cell discharges can be reversed by ERF stimulation. This interaction was not affected by cutting the dorsal roots at the place close to the recorded DRG. Preapplication of naloxone and yohimbine did not block the interaction. Taken together with previous reports, this intraganglionic cross-talking appears to be mediated by collision of retrograde spread of action potentials, or/and at least in part, by an activity-dependent diffusible excitatory substance released from neuronal somata and/or adjacent axons, and detected by neighboring cell somata.
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Affiliation(s)
- Guang-Yin Xu
- Marine Biomedical Institute, University of Texas Medical Branch, Galveston 77555-1069, USA
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30
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Amaya F, Oh-hashi K, Naruse Y, Iijima N, Ueda M, Shimosato G, Tominaga M, Tanaka Y, Tanaka M. Local inflammation increases vanilloid receptor 1 expression within distinct subgroups of DRG neurons. Brain Res 2003; 963:190-6. [PMID: 12560124 DOI: 10.1016/s0006-8993(02)03972-0] [Citation(s) in RCA: 176] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Vanilloid receptor 1 (VR1) is essential to the development of inflammatory hyperalgesia. We investigated whether inflammation can increase in VR1 positive neuronal profiles in rat DRG neurons using histochemical methods. We also used size frequency analysis and double staining with several neuronal markers to investigate whether or not inflammation alters VR1 expression. Inflammation induced a 1.5-fold increase in percentage of VR1-like immunoreactivity (LI) positive profiles per total neuronal profiles, suggesting that the number of heat and pH sensitive neurons increase during inflammation. Area frequency histograms showed that VR1 expression increased in small and medium-sized neurons after inflammation. Double labeling of VR1 with NF200 showed that VR1 positive neurons with NF200 positive profiles significantly increased, indicating that the medium-sized VR1 positive neurons were neurons with myelinated A-fibers. Local inflammation thus increases in VR1 protein level within distinct subgroups of DRG neurons that may participate in the development and maintenance of inflammatory hyperalgesia.
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Affiliation(s)
- Fumimasa Amaya
- Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kamikyo-ku, Kyoto, Japan
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31
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Häbler HJ, Jänig W. Reflexes in sympathetic vasoconstrictor neurones arising from urinary bladder afferents are not amplified early after inflammation in the anaesthetised cat. Pain 2003; 101:251-257. [PMID: 12583867 DOI: 10.1016/s0304-3959(02)00329-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Pathophysiological processes in the viscera can lead to pain and hyperalgesia and exaggerated motility-regulating reflexes. This may be due to sensitisation of visceral afferents (peripheral sensitisation), which has repeatedly been shown to occur as a consequence of e.g. inflammation, and/or to sensitisation of dorsal horn neurones (central sensitisation), which is less well documented in the visceral domain. As an indicator of peripheral sensitisation, we previously analysed the responses of sacral spinal afferents after inflammation of the urinary bladder. Here, we studied reflexes in sympathetic vasoconstrictor neurones supplying skeletal muscle and skin elicited by bladder distension stimuli (vesico-sympathetic reflexes) before and after induction of bladder inflammation. Our aim was to test whether these vesico-sympathetic reflexes are amplified after inflammation in a way that would support a major functional role for post-inflammatory central sensitisation processes. Bladder inflammation was induced in anaesthetised cats by instillation of turpentine or mustard oil and vesico-sympathetic reflexes were studied 1 and 2 h after induction of the inflammation. Inflammation enhanced on-going activity in vasoconstrictor neurones supplying skeletal muscle (after 1 h to 187.6+/-36.8%, mean+/-SEM, P<0.01, and after 2 h to 139.1+/-12.9%, P<0.05, of baseline activity) and decreased it in most sympathetic neurones supplying skin (to 91.7+/-12.5%, P>0.05, and to 71.6+/-11.3%, P<0.05, respectively, of baseline activity). Relative to the altered baseline activity vesico-sympathetic reflexes to graded distension of the inflamed bladder were quantitatively unchanged with a tendency to be diminished. Thus, the changes in on-going sympathetic vasoconstrictor activity and the distension-evoked reflexes directly mirrored the afferent input from the inflamed urinary bladder into the spinal cord, i.e. no increase of the gain of these reflexes was observed. These results suggest that in the first 2 h of inflammation, peripheral sensitisation processes play the main role for hyperalgesia and hyperreflexia of the urinary bladder. In contrast, central sensitisation appears to be of little importance during this time period.
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Affiliation(s)
- H-J Häbler
- Physiologisches Institut, Christian-Albrechts-Universität, Olshausenstrasse 40, D-24098 Kiel, Germany
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32
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Abstract
Widespread symptoms associated with the irritable bowel syndrome (IBS) are abnormal defecation and abdominal pain, both of which can be exacerbated by psychogenic stress. Disordered defecation may present as diarrhea or constipation. A subgroup of IBS patients alternate from one to the other over time. Urgency to stool often accompanies the diarrheal-state, and patients with the constipation-predominant form of IBS report straining and the feeling of incomplete evacuation. Basic scientific research aims for improved understanding of the physiology and pathophysiology of the digestive systems from which the arrays of IBS symptoms emerge. The key systems for the defecation-related symptoms are the intestinal secretory glands, the musculature, and the nervous system that controls and integrates their activity. Abdominal pain and discomfort arising from these systems adds the dimension of sensory neurophysiology. This review details current concepts of the underlying pathophysiology in terms of the physiology of intestinal secretion, motility, nervous control, sensing function, immuno-neural communication, and the brain-gut axis.
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Affiliation(s)
- Jackie D Wood
- Departments of Physiology and Cell Biology and Internal Medicine, Ohio State University College of Medicine and Public Health, Columbus, Ohio, USA.
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33
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Zhang C, Zhou Z. Ca(2+)-independent but voltage-dependent secretion in mammalian dorsal root ganglion neurons. Nat Neurosci 2002; 5:425-30. [PMID: 11953753 DOI: 10.1038/nn845] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2002] [Accepted: 03/05/2002] [Indexed: 11/08/2022]
Abstract
We have investigated the Ca(2+) dependence of vesicular secretion from the soma of dorsal root ganglion (DRG) neurons, which secrete neuropeptides by exocytosis of dense-core vesicles. In patch-clamped somata of rat DRG neurons, we found a depolarization-induced membrane capacitance increase (DeltaC(m)) in the absence of extracellular Ca(2+) and in the presence of a Ca(2+) chelator (BAPTA) in the intracellular solution. Depletion of internal Ca(2+) stores by thapsigargin in the Ca(2+)-free bath also did not block the DeltaC(m), indicating that Ca(2+) release from internal Ca(2+) stores may not have been involved. Furthermore, the Ca(2+)-independent DeltaC(m) was blocked by whole-cell dialysis with tetanus toxin and was accompanied by pulsatile secretion of false transmitters, as detected by amperometric measurements. These results indicate the existence of Ca(2+)-independent but voltage-dependent vesicular secretion (CIVDS) in a mammalian sensory neuron.
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Affiliation(s)
- C Zhang
- Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China
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34
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Coelho AM, Vergnolle N, Guiard B, Fioramonti J, Bueno L. Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats. Gastroenterology 2002; 122:1035-47. [PMID: 11910355 DOI: 10.1053/gast.2002.32387] [Citation(s) in RCA: 160] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS PAR-2s are highly expressed throughout the gastrointestinal tract. These receptors are cleaved by trypsin and mast cell tryptase and can be activated by peptides corresponding to the tethered ligand of the receptor (SLIGRL-NH2 for rat). The aim of this study was to determine whether colonic administration of PAR-2 agonists affects visceral sensitivity to rectal distention in conscious rats. METHODS Abdominal contractions (a criteria of visceral pain) were recorded in rats equipped with intramuscular electrodes. Rectal distention was performed at various times after intracolonic infusion of SLIGRL-NH2 and trypsin. Inflammation parameters and permeability were followed in the colon after the intracolonic injections. Fos expression at a spinal level (L4-L6) was also studied 2 hours after intracolonic injection of SLIGRL-NH2. RESULTS Rectal distention significantly increased abdominal contractions starting at the RD volume of 0.8 mL. Intracolonic injection of SLIGRL-NH2 (200 microg/rat) and trypsin (200 U/rat), but not vehicle, LRGILS-NH2 (control peptide), boiled trypsin, or SLIGRL-NH2 injected IP, significantly increased (P < 0.05) abdominal contractions for high volumes of distention, 10- and 24-hour postinfusion. SLIGRL-NH2-induced hyperalgesia was inhibited by a NK1 receptor antagonist (SR 140333) but not by indomethacin. Intracolonic injection of SLIGRL-NH2 elevated spinal Fos expression and caused increased intestinal permeability but did not cause detectable inflammation. CONCLUSIONS Intracolonic infusion of subinflammatory doses of PAR-2 agonists activated spinal afferent neurons and produced a delayed rectal hyperalgesia that involves changes in intestinal permeability and the activation of NK1 receptors. These results identify a possible role for proteinases and PAR-2 in the genesis of visceral hyperalgesia.
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Affiliation(s)
- Anne-Marie Coelho
- Neuro-Gastroenterology and Nutrition Unit, INRA, Toulouse Cedex, France
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35
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Abstract
ATP-gated P2X receptors in nociceptive sensory neurons participate in transmission of pain signals from the periphery to the spinal cord. To determine the role of P2X receptors under injurious conditions, we examined ATP-evoked responses in dorsal root ganglion (DRG) neurons isolated from rats with peripheral inflammation, induced by injections of complete Freund's adjuvant (CFA) into the hindpaw. Application of ATP induced both fast- and slow-inactivating currents in control and inflamed neurons. CFA treatment had no effect on the affinity of ATP for its receptors or receptor phenotypes. On the other hand, inflammation caused a twofold to threefold increase in both ATP-activated currents, altered the voltage dependence of P2X receptors, and enhanced the expression of P2X2 and P2X3 receptors. The increase in ATP responses gave rise to large depolarizations that exceeded the threshold of action potentials in inflamed DRG neurons. Thus, P2X receptor upregulation could account for neuronal hypersensitivity and contribute to abnormal pain responses associated with inflammatory injuries. These results suggest that P2X receptors are useful targets for inflammatory pain therapy.
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36
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Xu GY, Huang LYM. Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 2002; 22:93-102. [PMID: 11756492 PMCID: PMC6757597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2001] [Revised: 09/18/2001] [Accepted: 10/16/2001] [Indexed: 02/23/2023] Open
Abstract
ATP-gated P2X receptors in nociceptive sensory neurons participate in transmission of pain signals from the periphery to the spinal cord. To determine the role of P2X receptors under injurious conditions, we examined ATP-evoked responses in dorsal root ganglion (DRG) neurons isolated from rats with peripheral inflammation, induced by injections of complete Freund's adjuvant (CFA) into the hindpaw. Application of ATP induced both fast- and slow-inactivating currents in control and inflamed neurons. CFA treatment had no effect on the affinity of ATP for its receptors or receptor phenotypes. On the other hand, inflammation caused a twofold to threefold increase in both ATP-activated currents, altered the voltage dependence of P2X receptors, and enhanced the expression of P2X2 and P2X3 receptors. The increase in ATP responses gave rise to large depolarizations that exceeded the threshold of action potentials in inflamed DRG neurons. Thus, P2X receptor upregulation could account for neuronal hypersensitivity and contribute to abnormal pain responses associated with inflammatory injuries. These results suggest that P2X receptors are useful targets for inflammatory pain therapy.
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Affiliation(s)
- Guang-Yin Xu
- Marine Biomedical Institute and Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA
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37
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Xu GY, Zhao ZQ. Change in excitability and phenotype of substance P and its receptor in cat Abeta sensory neurons following peripheral inflammation. Brain Res 2001; 923:112-9. [PMID: 11743978 DOI: 10.1016/s0006-8993(01)03203-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The effect of peripheral inflammation on spontaneous firing and level of substance P (SP) and its receptor in electrophysiologically identified cat Abeta neurons of dorsal root ganglion (DRG) was studied in vivo using a combination of intracellular recording, dye injection and immunohistochemical techniques. Following injection of carrageenan (Carg) into cat hindpaw, the number of Abeta neurons with spontaneous firing was enhanced significantly (42.9%, n=182) in comparison with control (16.8%, n=149, P<0.01). DRG Abeta neurons became less depolarized 2-4 h following Carg injection. After identifying the cell properties, Lucifer Yellow was injected and SP-like immunoreactivity (SP-LI) was then detected. A total of 17% of Abeta sensory neurons exhibited SP-LI in inflammatory cat. We also found in rat DRGs that the number of SP-LI positive large cells (>35 microm) was also significantly increased in Carg-treated DRG (11.8+/-1.2, n=8) compared with untreated DRG (1.8+/-0.8, n=8, P<0.01). In control cat, the topical use of SP in DRG did not induce any response of Abeta neurons. However, in Carg-treated cat, SP depolarized the membrane potential in most Abeta neurons (68.2%, n=22). L668,169, an antagonist of SP receptor, completely blocked the SP-induced responses. Furthermore, repeated application of SP did not induce obvious desensitization of Abeta neurons. These data suggest that peripheral inflammation increased the excitability, SP level and sensitivity of SP receptor of Abeta neurons. Therefore, we concluded that Abeta sensory neurons appear to contribute to inflammatory allodynia.
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Affiliation(s)
- G Y Xu
- Shanghai Brain Research Institute, Chinese Academy of Sciences, Shanghai 200031, PR China
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38
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Time course and nerve growth factor dependence of inflammation-induced alterations in electrophysiological membrane properties in nociceptive primary afferent neurons. J Neurosci 2001. [PMID: 11698584 DOI: 10.1523/jneurosci.21-22-08722.2001] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Novel findings of changes in nociceptive dorsal root ganglion (DRG) neurons during hindlimb inflammation induced by complete Freund's adjuvant (CFA) injections in the hindpaw and hindleg are reported. These include increased maximum fiber following frequency in nociceptive C- and Adelta-fiber units by 2.7 and 3 times, respectively, and increased incidence of ongoing (spontaneous) activity by 3.3 times (to 54%) and 2.4 times (to 27%), respectively. These changes and the CFA-induced changes in somatic action potential (AP) configuration in nociceptive neurons (Djouhri and Lawson, 1999) were incomplete 24 hr after CFA. The nerve growth factor (NGF) dependence of the inflammation-induced changes was examined by injecting a synthetic NGF sequestering protein [tyrosine receptor kinase A Ig2 (trkA Ig2)] with CFA and subsequently into the CFA injection sites. NGF sequestration prevented some CFA-induced changes in nociceptive neurons including: the increased fiber following frequency (C and Adelta), the increased proportions of units with ongoing activity (C and Adelta), the decreased AP duration (C and Adelta), but not the decreased afterhyperpolarization (AHP) durations (C, Adelta, and Aalpha/beta) (Djouhri and Lawson, 1999). AP variables of nociceptive units with spontaneous activity were examined. The time course of electrophysiological changes in nociceptive units is consistent with processes involving altered protein expression and/or retrograde transport of factors. These results (1) implicate NGF in regulating inflammation-induced decreases in AP duration and in increases in firing rate and spontaneous activity but not in decreases in AHP duration and (2) suggest clinical advantages of reducing NGF in some inflammatory pain states.
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39
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Affiliation(s)
- W W Muir
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus 43210-1089, USA
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40
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Djouhri L, Dawbarn D, Robertson A, Newton R, Lawson SN. Time course and nerve growth factor dependence of inflammation-induced alterations in electrophysiological membrane properties in nociceptive primary afferent neurons. J Neurosci 2001; 21:8722-33. [PMID: 11698584 PMCID: PMC6762293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023] Open
Abstract
Novel findings of changes in nociceptive dorsal root ganglion (DRG) neurons during hindlimb inflammation induced by complete Freund's adjuvant (CFA) injections in the hindpaw and hindleg are reported. These include increased maximum fiber following frequency in nociceptive C- and Adelta-fiber units by 2.7 and 3 times, respectively, and increased incidence of ongoing (spontaneous) activity by 3.3 times (to 54%) and 2.4 times (to 27%), respectively. These changes and the CFA-induced changes in somatic action potential (AP) configuration in nociceptive neurons (Djouhri and Lawson, 1999) were incomplete 24 hr after CFA. The nerve growth factor (NGF) dependence of the inflammation-induced changes was examined by injecting a synthetic NGF sequestering protein [tyrosine receptor kinase A Ig2 (trkA Ig2)] with CFA and subsequently into the CFA injection sites. NGF sequestration prevented some CFA-induced changes in nociceptive neurons including: the increased fiber following frequency (C and Adelta), the increased proportions of units with ongoing activity (C and Adelta), the decreased AP duration (C and Adelta), but not the decreased afterhyperpolarization (AHP) durations (C, Adelta, and Aalpha/beta) (Djouhri and Lawson, 1999). AP variables of nociceptive units with spontaneous activity were examined. The time course of electrophysiological changes in nociceptive units is consistent with processes involving altered protein expression and/or retrograde transport of factors. These results (1) implicate NGF in regulating inflammation-induced decreases in AP duration and in increases in firing rate and spontaneous activity but not in decreases in AHP duration and (2) suggest clinical advantages of reducing NGF in some inflammatory pain states.
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Affiliation(s)
- L Djouhri
- Department of Physiology, University of Bristol, Medical School, University Walk, Bristol BS8 TD, United Kingdom.
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41
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Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD, Wallace JL. Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nat Med 2001; 7:821-6. [PMID: 11433347 DOI: 10.1038/89945] [Citation(s) in RCA: 364] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists. Here we identify a previously unrecognized nociceptive pathway with important therapeutic implications, and our results point to a direct role for proteinases and their receptors in pain transmission.
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Affiliation(s)
- N Vergnolle
- Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada
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42
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Abstract
Pain is necessary for survival, but persistent pain can result in anxiety, depression and a reduction in the quality of life. The discriminative and affective qualities of pain are both thought to be regulated in an activity-dependent fashion. Recent studies have identified cells and molecules that regulate pain sensitivity and the parallel pathways that distribute nociceptive information to limbic or sensory areas of the forebrain. Here, we emphasize the cellular and neurobiological consequences of pain, especially those that are involved in the generation and maintenance of chronic pain. These new insights into pain processing will significantly alter our approach to pain control and the development of new analgesics.
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Affiliation(s)
- S P Hunt
- Department of Anatomy and Developmental Biology, Medawar Building, University College London, Gower Street, London WC1E 6BT, UK.
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