Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABA Receptor Positive Allosteric Modulator.

Pain remains a challenging clinical condition and spinal GABA receptors are crucial modulators of pain processing. α2/α3-subtype GABA receptors mediate the analgesic actions of benzodiazepines. Positive allosteric modulators (PAMs) at α2/α3-subtype GABA receptors may have analgesic potential. Here we report a new selective α2/α3-subtype GABA receptor PAM in in vitro and in vivo pain assays. KRM-II-81 demonstrated similar efficacy at α1/α2/α3 GABA receptors and negligible efficacy at α4/α5/α6 GABA receptors, with α2 and α3-subtypes being 17- and 28-fold more potent than α1 subtypes in HEK-293T cells expressing GABA receptors with different α subunits. In contrast, KRM-II-18B showed significant efficacy at α1/α2/α3/ α5 subtypes, with similar potency at α1/α2/α3 subtypes. Both PAMs and morphine dose-dependently decreased 0.6% acetic acid- and 0.32% lactic acid-induced writhing. The effects of both PAMs were reversed by the benzodiazepine receptor antagonist flumazenil, confirming their action at the benzodiazepine binding site of GABA receptors. Both PAMS and morphine all dose-dependently reversed 0.32% lactic acid (but not 0.6% acetic acid) induced suppression of nesting behavior. Acetaminophen, but not the PAMs, reversed acid-depressed locomotor activity. Combined, these findings suggest that KRM-II-81 is a selective α2/α3 subtype GABA PAM with significant antinociceptive effects in chemical stimulation-induced pain in mice.