title: Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice.
abstract: Inhibition of spinal glutamate receptors induces antinociceptive effects in numerous animal models of pain. The present study compares the effects of intrathecally administered N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists on nociceptive responses in the tail flick test. Potency of antagonists at NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors was first measured by electrical assays in Xenopus oocytes expressing rat cerebral cortex poly(A)+ RNA. Subsequently, Swiss Webster mice were injected intrathecally with the antagonists and tested for antinociception. The drugs tested were: NBQX and GYKI-52466, selective AMPA receptor antagonists, ketamine, MK-801, R(+) HA-966 and ACEA-0762, selective NMDA receptor antagonists, and ACEA-1031, ACEA-1328 and ACEA-0593, NMDA receptor antagonists that also show inhibition of non-NMDA receptors. Selective NMDA receptor antagonists induced essentially no antinociceptive effects in the tail flick test. Antinociceptive activity generally correlated with inhibition of AMPA receptors. The exception was the non-competitive AMPA receptor antagonist GYKI-52466, which was unexpectedly weak. This may be due to inadequate dosing, because the compound has limited solubility, or may be due to differences in the non-NMDA receptor subtype-selectivity profile of GYKI-52466 as compared to competitive antagonists such as NBQX. Overall, our results suggest that inhibition of spinal non-NMDA receptors is the primary, and necessary, mechanism of antinociception by these drugs in the tail flick test in mice.
authors.affiliation: Department of Pharmacology, College of Medicine, University of California, Irvine 92717, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lutfy
authors.forename: S X
authors.initials: SX
authors.lastname: Cai
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
authors.forename: E
authors.initials: E
authors.lastname: Weber
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D017459:Receptors, Amino Acid / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013623:Tail / Q000503:physiopathology
chemical_list: D018091:Receptors, AMPA; D017459:Receptors, Amino Acid; D016194:Receptors, N-Methyl-D-Aspartate