title: α5GABAAReceptors Mediate Tonic Inhibition in the Spinal Cord Dorsal Horn and Contribute to the Resolution Of Hyperalgesia.
abstract: Neuronal inhibition mediated by GABAAreceptors constrains nociceptive processing in the spinal cord, and loss of GABAergic inhibition can produce allodynia and hyperalgesia. Extrasynaptic α5 subunit-containing GABAAreceptors (α5GABAARs) generate a tonic conductance that inhibits neuronal activity and constrains learning and memory; however, it is unclear whether α5GABAARs similarly generate a tonic conductance in the spinal cord dorsal horn to constrain nociception. We assessed the distribution of α5GABAARs in the spinal cord dorsal horn by immunohistochemical analysis, and the activity and function of α5GABAARs in neurons of the superficial dorsal horn using electrophysiological and behavioral approaches in male, null-mutant mice lacking the GABAAR α5 subunit (Gabra5-/-) and wild-type mice (WT). The expression of α5GABAARs in the superficial dorsal horn followed a laminar pattern of distribution, with a higher expression in lamina II than lamina I. Similarly, the tonic GABAAcurrent in lamina II neurons had a larger contribution from α5GABAARs than in lamina I, with no significant contribution of these receptors to synaptic GABAAcurrent. In behavioural tests, WT and Gabra5-/- mice exhibited similar acute thermal and mechanical nociception, and similar mechanical sensitization immediately following intraplantar capsaicin or Complete Freund's Adjuvant (CFA). However, Gabra5-/- mice showed prolonged recovery from sensitization in these models, and increased responses in the late phase of the formalin test. Overall, our data suggest that tonically-active α5GABAARs in the spinal cord dorsal horn accelerate the resolution of hyperalgesia and may therefore serve as a novel therapeutic target to promote recovery from pathological pain. © 2016 Wiley Periodicals, Inc.
authors: Institut Universitaire en Santé Mentale de Québec, Québec, Canada.
authors: Jimena
authors: J
authors: Perez-Sanchez
authors: Institut Universitaire en Santé Mentale de Québec, Québec, Canada.
authors: Louis-Etienne
authors: LE
authors: Lorenzo
authors: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors: Irene
authors: I
authors: Lecker
authors: University of Toronto, Department of Physiology, Toronto, Ontario, Canada.
authors: Agnieszka A
authors: AA
authors: Zurek
authors: Department of Biological Applications and Technology, University of Ioannina, Ioannina, Greece.
authors: Charalampos
authors: C
authors: Labrakakis
authors: University of Toronto, Department of Physiology, Toronto, Ontario, Canada.
authors: Erica M
authors: EM
authors: Bridgwater
authors: University of Toronto, Department of Physiology, Toronto, Ontario, Canada.|University of Toronto, Department of Anesthesia, Toronto, Ontario, Canada.|Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors: Beverley A
authors: BA
authors: Orser
authors: Institut Universitaire en Santé Mentale de Québec, Québec, Canada.|Department of Psychiatry and Neuroscience, Université Laval, Québec, Canada.
authors: Yves
authors: Y
authors: De Koninck
authors: Institut Universitaire en Santé Mentale de Québec, Québec, Canada.|Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors: Robert P
authors: 0000-0002-3287-6803
authors: RP
authors: Bonin
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000633:toxicity; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D018682:GABA Agents / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D037102:Lectins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement; D010812:Physical Stimulation / Q000009:adverse effects; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D018682:GABA Agents; C496250:Gabra5 protein, mouse; D037102:Lectins; D008565:Membrane Proteins; D011963:Receptors, GABA-A; C073441:gephyrin; D005620:Freund's Adjuvant; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D001640:Bicuculline
keywords: GABA; dorsal horn; inhibition; nociception; sensitization