α5GABAAReceptors Mediate Tonic Inhibition in the Spinal Cord Dorsal Horn and Contribute to the Resolution Of Hyperalgesia

AbstractNeuronal 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 andGabra5−/−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.