The utility of excitatory amino acid (EAA) antagonists as analgesic agents. II. Assessment of the antinociceptive activity of combinations of competitive and non-competitive NMDA antagonists with agents acting at allosteric-glycine and polyamine receptor sites.

The present study examined the utility of using low-dose combinations of agents acting within the NMDA receptor complex to produce analgesic effects without producing motor dysfunction. In particular, we assessed the antinociceptive activity in the formalin test of combinations of competitive (APV) and non-competitive (MK-801) NMDA receptor antagonists with agonist and antagonists acting at allosteric-glycine and polyamine receptors. Both the competitive NMDA receptor antagonist APV and the non-competitive NMDA antagonist MK-801 produced dose-dependent analgesic effects in the late, but not the early, phase of the formalin test. The antinociceptive activity of APV was significantly enhanced by combination with a non-analgesic dose of the allosteric-glycine agonist glycine, and was reduced by combination with the allosteric-glycine antagonist 7-CKA which also reversed the glycine-induced enhancement of the antinociceptive effects of APV. The antinociceptive activity of MK-801 was significantly enhanced by combination with a non-analgesic dose of the polyamine agonist spermine, and reduced by combination with the polyamine receptor antagonist IFEN which also reversed the spermine-induced enhancement of the antinociceptive effects of MK-801. The enhancement of the antinociceptive activity of APV and MK-801 by glycine and spermine, respectively, was not accompanied by increases in motor dysfunction. Thus, by using specific combination of agents acting within the NMDA receptor complex, it was possible to produce effective antinociception in the formalin test at doses of NMDA receptor antagonists which did not produce motor dysfunction.