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Updated: Jun 27, 2025
Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Antinociceptive Effects of α2/α3-Subtype-Selective GABAA Receptor Positive Allosteric Modulators KRM-II-81 and
Lakeisha A Lewter1, Kristen Woodhouse1, V V N Phani Babu Tiruveedhula1
1Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York (L.A.L., K.W., J.-X.L.); and Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (V.V.N.P.B.T., J.M.C.).
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Recent studies suggest that among the gamma-aminobutyric acid type A (GABAA)receptor subtype heterogeneity, α2/α3 subunits of GABAA receptors mediate pain processing. Therefore, α2/α3 subtype-selective GABAA receptor-positive allosteric modulators (PAMs) may be candidate analgesics. Antinociceptive effects of α2/α3 subtype-selective GABAA 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 GABAA 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 GABAA PAMs could be a novel class of analgesics and warrant further investigation. SIGNIFICANCE STATEMENT: This study demonstrates that α2/α3 subtype-selective GABAA 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 GABAA PAMs, rather than classical benzodiazepines, as safe and novel analgesics for pain management.
