Abstract
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.
Footnotes
- Received December 20, 2023.
- Accepted April 15, 2024.
This work was supported by National Institutes of Health National Institute on Drug Abuse [Grants R01DA034806 and R01DA047967]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
No author reported a conflict of interest with the information presented in this manuscript.
These results were part of the PhD dissertation of the first author, Lakeisha Lewter, and the full dissertation can be accessed from ProQuest database (https://www.proquest.com/pqdtglobal/docview/2194394707/87A8E872B9104ABFPQ/2?accountid=14169&sourcetype=Dissertations%20&%20Theses).
- Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics
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