The α5 subunit containing GABAA receptors contribute to chronic pain

It has been recently proposed that alpha(5)-subunit containing GABA(A) receptors (alpha(5)-GABA(A) receptors) that mediate tonic inhibition might be involved in pain. The purpose of this study was to investigate the contribution of alpha(5)-GABA(A) receptors in the loss of GABAergic inhibition and in formalin-induced, complete Freund's adjuvant (CFA)-induced and L5 and L6 spinal nerve ligation-induced longlasting hypersensitivity. Formalin or CFA injection and L5 and L6 spinal nerve ligation produced long-lasting allodynia and hyperalgesia. Moreover, formalin injection impaired the rate-dependent depression of the Hofmann reflex. Peripheral and intrathecal pretreatment or post-treatment with the alpha(5)-GABA(A) receptor antagonist, L-655,708 (0.15-15 nmol), prevented and reversed, respectively, these long-lasting behaviors. Formalin injection increased alpha(5)-GABA(A) receptor mRNA expression in the spinal cord and dorsal root ganglia (DRG) mainly at 3 days. The alpha(5)-GABA(A) receptors were localized in the dorsal spinal cord and DRG colabeling with NeuN, CGRP, and IB4 which suggests their presence in peptidergic and nonpeptidergic neurons. These receptors were found mainly in small and medium sized neurons. Formalin injection enhanced alpha(5)-GABA(A) receptor fluorescence intensity in spinal cord and DRG at 3 and 6 days. Intrathecal administration of L-655,708 (15 nmol) prevented and reversed formalin-induced impairment of rate-dependent depression. These results suggest that alpha(5)-GABA(A) receptors play a role in the loss of GABAergic inhibition and contribute to long-lasting secondary allodynia and hyperalgesia.