Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABAAReceptor Positive Allosteric Modulator.
Pain remains a challenging clinical condition and spinal GABAAreceptors are crucial modulators of pain processing. α2/α3-subtype GABAAreceptors mediate the analgesic actions of benzodiazepines. Positive allosteric modulators (PAMs) at α2/α3-subtype GABAAreceptors may have analgesic potential. Here we report a new selective α2/α3-subtype GABAAreceptor PAM in in vitro and in vivo pain assays. KRM-II-81 demonstrated similar efficacy at α1/α2/α3 GABAAreceptors and negligible efficacy at α4/α5/α6 GABAAreceptors, with α2 and α3-subtypes being 17- and 28-fold more potent than α1 subtypes in HEK-293T cells expressing GABAAreceptors 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 GABAAreceptors. 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 GABAAPAM with significant antinociceptive effects in chemical stimulation-induced pain in mice.
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York 14214, United States.
Lakeisha A
LA
Lewter
Department of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina , Columbia, South Carolina 29208, United States.
Janet L
JL
Fisher
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York 14214, United States.
Justin N
JN
Siemian
Department of Chemistry, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53211, United States.
Kashi Reddy
KR
Methuku
Department of Chemistry, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53211, United States.
Michael M
MM
Poe
Department of Chemistry, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53211, United States.
James M
0000-0001-5512-3022
JM
Cook
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York 14214, United States.
Jun-Xu
0000-0001-8103-7013
JX
Li
D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010080:Oxazoles / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects*
D000700:Analgesics; D058785:GABA-A Receptor Agonists; C000620331:KRM-II-81; D010080:Oxazoles; D011963:Receptors, GABA-A
GABAA; mice; nesting; pain; positive allosteric modulator; writhing