α5GABAA Receptors Mediate Tonic Inhibition in the Spinal Cord Dorsal Horn and Contribute to the Resolution Of Hyperalgesia

Neuronal inhibition mediated by GABA(A) receptors constrains nociceptive processing in the spinal cord, and loss of GABAergic inhibition can produce allodynia and hyperalgesia. Extrasynaptic 5 subunit-containing GABA(A) receptors (5GABA(A)Rs) generate a tonic conductance that inhibits neuronal activity and constrains learning and memory; however, it is unclear whether 5GABA(A)Rs similarly generate a tonic conductance in the spinal cord dorsal horn to constrain nociception. We assessed the distribution of 5GABA(A)Rs in the spinal cord dorsal horn by immunohistochemical analysis, and the activity and function of 5GABA(A)Rs in neurons of the superficial dorsal horn using electrophysiological and behavioral approaches in male, null-mutant mice lacking the GABA(A)R 5 subunit (Gabra5-/-) and wild-type mice (WT). The expression of 5GABA(A)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(A) current in lamina II neurons had a larger contribution from 5GABA(A)Rs than in lamina I, with no significant contribution of these receptors to synaptic GABA(A) 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 5GABA(A)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. (c) 2016 Wiley Periodicals, Inc.