Pharmacological enhancement of δ-subunit-containing GABAA receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice

The development of new strategies for the treatment of acute pain requires the identification of novel nonopioid receptor targets. This study explored whether δ-subunit-containing GABAARs (δGABAARs) in neurons of the spinal cord dorsal horn generate a tonic inhibitory conductance in vitro and whether δGABAAR activity regulates acute nociception. Whole-cell recordings revealed that δGABAARs generate a tonic inhibitory conductance in cultured spinal neurons and lamina II neurons in spinal cord slices. Increasing δGABAAR function by applying the δGABAAR-preferring agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol (THIP) increased the tonic current and inhibited neuronal excitability in spinal neurons from wild-type (WT) but not δ subunit null-mutant (Gabrd−/−) mice. In behavioral studies, baseline δGABAAR activity did not regulate acute nociception; however, THIP administered intraperitoneally or intrathecally attenuated acute nociception in WT but not Gabrd−/− mice. In the formalin nociception assay, the phase 1 response was similar for WT and Gabrd−/− mice. In contrast, the phase 2 response, which models central sensitization, was greater in Gabrd−/− mice than WT. THIP administered intraperitoneally or intrathecally inhibited phase 1 responses of WT but not Gabrd−/− mice and had no effect on phase 2 responses of WT mice. Surprisingly, THIP reduced the enhanced phase 2 response in Gabrd−/− mice. Together, these results suggest that δGABAARs in spinal neurons play a major physiological and pharmacological role in the regulation of acute nociception and central sensitization.