TY - JOUR T1 - α5GABA Receptors Mediate Tonic Inhibition in the Spinal Cord Dorsal Horn and Contribute to the Resolution Of Hyperalgesia. JF - J Neurosci Res Y1 - 2017 A1 - Perez-Sanchez, Jimena A1 - Lorenzo, Louis-Etienne A1 - Lecker, Irene A1 - Zurek, Agnieszka A A1 - Labrakakis, Charalampos A1 - Bridgwater, Erica M A1 - Orser, Beverley A A1 - De Koninck, Yves A1 - Bonin, Robert P KW - Animals KW - Bicuculline KW - Calcitonin Gene-Related Peptide KW - Capsaicin KW - Carrier Proteins KW - Disease Models, Animal KW - Freund's Adjuvant KW - GABA Agents KW - Hyperalgesia KW - In Vitro Techniques KW - Inhibitory Postsynaptic Potentials KW - Lectins KW - Male KW - Membrane Proteins KW - Mice KW - Mice, Inbred C57BL KW - Mice, Transgenic KW - Neural Inhibition KW - Neurons KW - Pain Measurement KW - Physical Stimulation KW - Receptors, GABA-A KW - Spinal Cord Dorsal Horn AB -

Neuronal inhibition mediated by GABA receptors constrains nociceptive processing in the spinal cord, and loss of GABAergic inhibition can produce allodynia and hyperalgesia. Extrasynaptic α5 subunit-containing GABA receptors (α5GABA Rs) generate a tonic conductance that inhibits neuronal activity and constrains learning and memory; however, it is unclear whether α5GABA Rs similarly generate a tonic conductance in the spinal cord dorsal horn to constrain nociception. We assessed the distribution of α5GABA Rs in the spinal cord dorsal horn by immunohistochemical analysis, and the activity and function of α5GABA Rs in neurons of the superficial dorsal horn using electrophysiological and behavioral approaches in male, null-mutant mice lacking the GABA R α5 subunit (Gabra5-/-) and wild-type mice (WT). The expression of α5GABA Rs in the superficial dorsal horn followed a laminar pattern of distribution, with a higher expression in lamina II than lamina I. Similarly, the tonic GABA current in lamina II neurons had a larger contribution from α5GABA Rs than in lamina I, with no significant contribution of these receptors to synaptic GABA current. 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 α5GABA Rs 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.

VL - 95 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/27792253?dopt=Abstract ER -