THE UTILITY OF EXCITATORY AMINO-ACID (EAA) ANTAGONISTS AS ANALGESIC AGENTS .2. ASSESSMENT OF THE ANTINOCICEPTIVE ACTIVITY OF COMBINATIONS OF COMPETITIVE AND NONCOMPETITIVE 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 assess ed the antinociceptive activity in the formalin test of combinations o f competitive (APV) and non-competitive (MK-801) NMDA receptor antagon ists with agonist and antagonists acting at allosteric-glycine and pol yamine receptors. Both the competitive NMDA receptor antagonist APV an d the non-competitive NMDA antagonist MK-801 produced dose-dependent a nalgesic 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 ago nist glycine, and was reduced by combination with the allosteric-glyci ne antagonist 7-CKA which also reversed the glycine-induced enhancemen t of the antinociceptive effects of APV. The antinociceptive activity of MK-801 was significantly enhanced by combination with a non-analges ic dose of the polyamine agonist spermine, and reduced by combination with the polyamine receptor antagonist IFEN which also reversed the sp ermine-induced enhancement of the antinociceptive effects of MK-801. T he enhancement of the antinociceptive activity of APV and MK-801 by gl ycine and spermine, respectively, was not accompanied by increases in motor dysfunction. Thus, by using specific combination of agents actin g within the NMDA receptor complex, it was possible to produce effecti ve antinociception in the formalin test at doses of NMDA receptor anta gonists which did not produce motor dysfunction.