Spinal antinociceptive effects of excitatory amino acid antagonists: quisqualate modulates the action of N-methyl-D-aspartate

Abstract

Blockade of N-methyl-D-aspartate (NMDA) receptors in the spinal cord of rodents has been shown to produce antinociceptive effects and motor impairment. To find out whether other receptors for excitatory amino acids (EAA) can influence spinal pathways utilizing the NMDA receptors we compared, in mice, the behavioral consequences of intrathecal injection of four EAA antagonists, 2-amino-5-phosphono valerate (APV), kynurenate, γ-D-glutamyl glycine (DGG) and glutamylaminomethyl sulphonate (GAMS). The selectivity of these antagonists at different concentrations was evaluated behaviorally by assessing their ability to block the biting behavior elicited by intrathecal EAA agonists. Blockade of the NMDA receptor was necessary to elicit antinociceptive effects and motor impairment. Thus, APV produced antinociception at concentrations selective for the action of NMDA. The wide spectrum EAA antagonists, DGG and kynurenate, and the quiqualate/kainate antagonist, GAMS, all produced antinociception and motor impairment at concentrations which also blocked NMDA-induced bites. However, an inhibitory modulation of the action of NMDA by quisqualate-sensitive systems was also observed. Thus, high concentrations of APV (> 1 mM) which also blocked quisqualate-elicited bites, produced a surprising, sharp decrease in APV antinociception and motor impairment, effects which were reversed by quisqualate. Furthermore, quisqualate significantly inhibited NMDA-induced bites. Additional evidence for such an inhibitory-modulatory effect of quisqualate can be gathered from the antinociceptive potency of DGG. This antagonist, which blocks the action of both NMDA and quisqualate, was less potent as an antinociceptive agent than APV. No such discrepancy between the ability to inhibit the action of NMDA and to elicit antinociceptive effects and motor impairment was noted for either kynurenate or GAMS. Evidence is provided that these different profiles of action are due to the fact that DGG and high concentrations of APV act at different subpopulations of quisqualate receptors than do kynurenate and GAMS, and that the former subpopulation is involved in the modulation of the action of NMDA.