Inhibition of α5 subunit-containing GABAA receptors facilitated spinal nociceptive transmission and plasticity.

Abstract

γ-Aminobutyric acid (GABA) type A receptors (GABAA Rs) locate at both synaptic and extrasynaptic membrane, which generate phasic and tonic inhibition, respectively. In spinal cord dorsal horn, the phasic inhibition produced by transient activation of synaptic GABAA Rs plays an important role in the gating control over nociceptive conveyance. Although extrasynaptic GABAA Rs that contain α5 subunits (α5-GABAA Rs) are also detectable in spinal dorsal horn, much less is known about the function of these receptors. The C fibre-evoked field potentials were recorded in superficial dorsal horn of spinal cord, and the effects of α5-GABAA R inverse agonist L-655708 on basal synaptic transmission and long-term potentiation (LTP) of C-fibre responses were examined. The possible changes of glutamate receptor function and pain sensitivity after α5-GABAA R inhibition were investigated by western blot and behavioural tests. Inhibition of α5-GABAA Rs by L-655708 boosted the basal synaptic transmission and facilitated the induction of N-methyl-d-aspartate subtype glutamate receptors (NMDARs)-dependent LTP. L-655708 was found to enhance the phosphorylation and synaptic accumulation of NMDARs and α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid receptors (AMPARs). Intrathecal L-655708 injection also decreased the pain thresholds of intact mice in a dose-dependent manner. α5-GABAA Rs were critical for the tonic inhibition of glutamatergic neurotransmission and plasticity in spinal dorsal horn. Tonic inhibition generated by α5-GABAA Rs is important for information processing. However, whether and how α5-GABAA Rs regulate the conveyance of nociceptive signals in spinal cord is largely unknown. Here, we revealed a negative control by α5-GABAA Rs over nociceptive transmission and plasticity.