Allosteric modulators of the δ GABAA receptor subtype demonstrate a therapeutic effect in morphine-antinociceptive tolerance and withdrawal in mice

K Genaro; R F Yoshimura; B P Doan; T B Johnstone; D J Hogenkamp; K W Gee

doi:10.1016/j.neuropharm.2022.109221

Allosteric modulators of the δ GABA_A receptor subtype demonstrate a therapeutic effect in morphine-antinociceptive tolerance and withdrawal in mice

Neuropharmacology. 2022 Nov 15:219:109221. doi: 10.1016/j.neuropharm.2022.109221. Epub 2022 Sep 7.

Authors

K Genaro¹, R F Yoshimura², B P Doan³, T B Johnstone⁴, D J Hogenkamp⁴, K W Gee⁴

Affiliations

¹ Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, 92697-4625, USA; Department of Anesthesiology, School of Medicine, University of California, Irvine, CA, 92697, USA. Electronic address: kgenaro@hs.uci.edu.
² Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, 92697-4625, USA. Electronic address: ryoshimu@uci.edu.
³ Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, 92697-4625, USA; Department of Anesthesiology, School of Medicine, University of California, Irvine, CA, 92697, USA.
⁴ Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, 92697-4625, USA.

Abstract

The present study evaluated the effects of compounds targeting extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ*-GABA_ARs) to interrogate the role of tonic inhibition in the development of antinociceptive tolerance caused by repeated morphine administration. We investigated the effect of subchronic or acute treatment with non-steroidal positive allosteric modulators (PAMs) of δ*-GABA_ARs, such as 2-261, on the morphine-antinociceptive tolerance. Mice were treated twice daily with morphine for 9 days and antinociception was measured using the hot water tail immersion test. Co-treatment with 2-261 and morphine prevented morphine-antinociceptive tolerance and acute administration of 2-261 on day 9 was sufficient to reverse the tolerance. Other compounds with activity at δ*-GABA_ARs also reversed morphine tolerance, whereas an enaminone that lacked activity at δ*-GABA_ARs did not. Acute administration of 2-261 did not cause an additive or synergistic antinociceptive effect when combined with an acute submaximal dose of morphine. We then used Cre/LoxP recombination to generate GABA_A δ-subunit knockout mice to corroborate the pharmacological results. Observations of male δ-knockout mice demonstrated that the δ*-GABA_ARs was necessary for 2-261 modulation of both analgesic tolerance and somatic withdrawal symptoms produced by subchronic morphine. While female mice still benefited from the positive effects of 2-261, the δ-subunit was not necessary for these effects, highlighting a distinction of the different pathways that could have implications for some of the sex-related differences seen in human opioid-induced outcomes. Consequently, subtype-specific allosteric modulators of GABA_ARs may warrant further investigation as pharmacological targets to manage tolerance and withdrawal from opioids.

Keywords: Morphine-antinociceptive tolerance; Opioid; Opioid withdrawal symptoms; Positive allosteric modulators; δ-subunit GABA(A) receptor.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Analgesics / pharmacology
Analgesics, Opioid* / pharmacology
Animals
Dose-Response Relationship, Drug
Female
Humans
Male
Mice
Mice, Knockout
Morphine*
Receptors, GABA-A
Receptors, Opioid, delta
Water
gamma-Aminobutyric Acid

Substances

Analgesics
Analgesics, Opioid
Receptors, GABA-A
Receptors, Opioid, delta
Water
gamma-Aminobutyric Acid
Morphine

Grants and funding

R01 DA041454/DA/NIDA NIH HHS/United States