Antinociceptive Effects of α 2/ α 3-Subtype-Selective GABAA Receptor Positive Allosteric Modulators KRM-II-81 and NS16085 in Male Rats: Behavioral Specificity

Abstract

Recent studies suggest that among the gamma-aminobutyric acid type A (GABA_A)receptor subtype heterogeneity, α2/α3 subunits of GABA_A receptors mediate pain processing. Therefore, α2/α3 subtype-selective GABA_A receptor-positive allosteric modulators (PAMs) may be candidate analgesics. Antinociceptive effects of α2/α3 subtype-selective GABA_A receptor PAMs have been reported, but the behavioral effects of these compounds have not been systematically evaluated. This study examined the behavioral effects of two α2/α3 subtype-selective GABA_A receptor PAMs, KRM-II-81 and NS16085, in male rats. The antinociceptive effects of KRM-II-81 and NS16085 were examined using rat models of inflammatory (complete Freund's adjuvant) and neuropathic pain (chronic constriction injury). The effect of KRM-II-81 on affective pain was measured using the place escape/avoidance paradigm (PEAP). Rate-response of food-maintained operant responding, horizontal wire test, and the spontaneous alternation T-maze were assessed to study the side-effect profiles of KRM-II-81 and NS16085. The benzodiazepine midazolam was used as a comparator in these studies. KRM-II-81 and NS16085 attenuated mechanical allodynia but not thermal hyperalgesia in both pain states, and their effects were attenuated by the benzodiazepine receptor antagonist flumazenil. KRM-II-81 attenuated affective pain-related behavior in the PEAP test. In the operant responding procedure and horizontal wire test, only midazolam produced significant effects at the dose that produced maximal antinociception. In the T-maze assay, only midazolam significantly decreased the percentage of alternation at an antinociceptive dose. Thus, KRM-II-81 and NS16085 but not midazolam selectively produced antinociceptive effects. Collectively, these data suggest that α2/α3 subtype-selective GABA_A PAMs could be a novel class of analgesics and warrant further investigation. SIGNIFICANCE STATEMENT: This study demonstrates that α2/α3 subtype-selective GABA_A PAMs KRM-II-81 and NS16085 produce selective antinociceptive effects devoid of sedation, myorelaxation, and cognitive impairment in two rat models of persistent pain. This study supports the development of α2/α3 subtype-selective GABA_A PAMs, rather than classical benzodiazepines, as safe and novel analgesics for pain management.