Faculty Collaboration Database

Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABA_A Receptor Positive Allosteric Modulator. ACS Chem Neurosci 2017 Jun 21;8(6):1305-1312

Date

02/06/2017

Pubmed ID

28150939

Pubmed Central ID

PMC5686453

DOI

10.1021/acschemneuro.6b00447

Scopus ID

2-s2.0-85019846739 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

Pain remains a challenging clinical condition and spinal GABA_A receptors are crucial modulators of pain processing. α2/α3-subtype GABA_A receptors mediate the analgesic actions of benzodiazepines. Positive allosteric modulators (PAMs) at α2/α3-subtype GABA_A receptors may have analgesic potential. Here we report a new selective α2/α3-subtype GABA_A receptor PAM in in vitro and in vivo pain assays. KRM-II-81 demonstrated similar efficacy at α1/α2/α3 GABA_A receptors and negligible efficacy at α4/α5/α6 GABA_A receptors, with α2 and α3-subtypes being 17- and 28-fold more potent than α1 subtypes in HEK-293T cells expressing GABA_A 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_A 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_A PAM with significant antinociceptive effects in chemical stimulation-induced pain in mice.

Author List

Lewter LA, Fisher JL, Siemian JN, Methuku KR, Poe MM, Cook JM, Li JX

Author

James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Allosteric Regulation
Allosteric Site
Analgesics
Animals
GABA-A Receptor Agonists
HEK293 Cells
Humans
Male
Mice
Mice, Inbred ICR
Oxazoles
Receptors, GABA-A