Spinal Nerve Ligation in Mouse Upregulates TRPV1 Heat Function in Injured IB4-Positive Nociceptors |
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| Authors: | Daniel Vilceanu Prisca Honore Quinn H Hogan Cheryl L Stucky |
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| Institution: | 1. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin;2. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin;3. Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois;1. Neurological Unit, University-Hospital “S. Maria della Misericordia”, Udine, Italy;2. Neuroalgology and Headache Unit, IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy;3. Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands;4. Department of Neurology, Spaarne Hospital, Hoofddorp, The Netherlands;5. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, and Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT, USA;1. Renal Section, North Florida/South Georgia Veterans Health System, Gainesville, FL, United States;2. Division of Nephrology, Hypertension & Transplantation, Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100224, Gainesville, FL 32610-0266, United States;3. Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, United States;4. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States;5. Division of Renal Diseases and Hypertension, University of Colorado-Denver, Aurora, CO, United States;1. Maternal and Fetal Health Research Centre, Institute of Human Development, The University of Manchester, Manchester Academic Health Science Centre, St. Mary''s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, United Kingdom;2. School of Nursing, Midwifery and Social Work, The University of Manchester, Jean McFarlane Building, Oxford Road, Manchester M13 9PL, United Kingdom;3. Department of Biology, Ecology and Earth Sciences, University of Calabria, Arcavacata di Rende, CS, Italy;4. Pcovery Aps, Thorvaldsensvej 57, DK-1871 Frederiksberg C, Denmark;1. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada;2. Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada;3. Department of Psychology, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada;4. Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada;5. Centre de Recherche du Centre Hospitalier de L’Universite Laval, Quebec, Quebec, Canada;6. Faculty of Dentistry, McGill University, Montreal, Quebec, Canada;1. Department of Anesthesia and Pain Medicine Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas;2. Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas;1. Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan |
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| Abstract: | Peripheral nerve injury leads to neuropathic pain, but the underlying mechanisms are not clear. The TRPV1 channel expressed by nociceptors is one receptor for noxious heat and inflammatory molecules. Lumbar 4 (L4) spinal nerve ligation (SNL) in mice induced persistent heat hyperalgesia 4 to 10 days after injury. The heat hypersensitivity was completely reversed by the TRPV1 antagonist A-425619. Furthermore, DRG neurons were isolated from the injured L4 ganglia or adjacent L3 ganglia 4 to 10 days after L4 SNL. Whole-cell patch-clamp recordings were performed and heat stimuli (22°C to 50°C/3 s) were applied to the soma. Neurons were classified by soma size and isolectin-B4 (IB4) binding. Among directly injured L4 neurons, SNL increased the percentage of small-diameter IB4-positive neurons that were heat-sensitive from 13% (naive controls) to 56% and conversely decreased the proportion of small IB4-negative neurons that were heat-sensitive from 66% (naive controls) to 34%. There was no change in IB4 binding in neurons from the injured ganglia. Surprisingly, in neurons from the adjacent L3 ganglia, SNL had no effect on the heat responsiveness of either IB4-positive or negative small neurons. Also, SNL had no effect on heat responses in medium-large–diameter neurons from either the injured or adjacent ganglia.PerspectiveTRPV1 function is upregulated in IB4-positive sensory neurons, and TRPV1 is responsible for the behavioral heat hypersensitivity in the spinal nerve ligation model. Because IB4-positive neurons may contribute to the emotional perception of pain, TRPV1 antagonists, targeting both sensory and affective pain components, could have broad analgesic effects. |
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