Inhibition of α5 subunit‐containing GABA A receptors facilitated spinal nociceptive transmission and plasticity

Background γ‐Aminobutyric acid ( GABA ) type A receptors ( GABA A R s) 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 GABA A R s plays an important role in the gating control over nociceptive conveyance. Although extrasynaptic GABA A R s that contain α5 subunits (α5‐ GABA A R s) are also detectable in spinal dorsal horn, much less is known about the function of these receptors. Methods The C fibre‐evoked field potentials were recorded in superficial dorsal horn of spinal cord, and the effects of α5‐ GABA A 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‐ GABA A R inhibition were investigated by western blot and behavioural tests. Results Inhibition of α5‐ GABA A R s by L‐655708 boosted the basal synaptic transmission and facilitated the induction of N‐methyl‐ d ‐aspartate subtype glutamate receptors ( NMDAR s)‐dependent LTP . L‐655708 was found to enhance the phosphorylation and synaptic accumulation of NMDAR s and α‐Amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic Acid receptors ( AMPAR s). Intrathecal L‐655708 injection also decreased the pain thresholds of intact mice in a dose‐dependent manner. Conclusions α5‐ GABA A R s were critical for the tonic inhibition of glutamatergic neurotransmission and plasticity in spinal dorsal horn. Significance Tonic inhibition generated by α5‐ GABA A R s is important for information processing. However, whether and how α5‐ GABA A R s regulate the conveyance of nociceptive signals in spinal cord is largely unknown. Here, we revealed a negative control by α5‐ GABA A R s over nociceptive transmission and plasticity.