THE UTILITY OF EXCITATORY AMINO-ACID (EAA) ANTAGONISTS AS ANALGESIC AGENTS .1. COMPARISON OF THE ANTINOCICEPTIVE ACTIVITY OF VARIOUS CLASSES OF EAA ANTAGONISTS IN MECHANICAL, THERMAL AND CHEMICAL NOCICEPTIVE TESTS

The present study was performed to assess the utility of excitatory am ino acid (EAA) antagonists as analgesia agents, The antinociceptive ac tivity of various classes of EAA antagonists was assessed in mechanica l and thermal flexion reflexes tests, as well as in the formalin test. Additional testing assessed the motor dysfunction associated with ant inociceptive dose levels of the agents used, by examining placing, gra sping and righting reflexes, as well as occurrences of balance loss du ring locomotion. No antinociceptive activity was observed on any of th e nociceptive measures for the non-NMDA receptor antagonists CNQX or L -AP-3. High doses of the non-competitive (PCP-site) NMDA receptor anta gonist MK-801 and the allosteric-glycine receptor antagonist 7-CKA pro duced antinociception on both the mechanical and thermal flexion refle x measures, while a high dose of the competitive NMDA receptor antagon ist CPP produced antinociception only on the thermal flexion reflex me asure. Hyperalgesic effects on thermal flexion reflexes were obtained with all doses of the polyamine receptor antagonist ARCA, and with the highest dose of the allosteric-glycine receptor antagonist FICA. Form alin nociceptive behaviours were significantly reduced only by high do ses of competitive (APV) and non-competitive (MK-801) NMDA receptor an tagonists. The doses of EAA receptor antagonists which produced antino ciceptive effects on any of the 3 nociceptive tests also produced evid ence of motor dysfunction. Both competitive NMDA receptor antagonists (APV and CPP) produced disruptions of placing, grasping and righting r eflexes: while 2 of the allosteric-glycine receptor antagonists (7-CKA and DCQX) significantly disrupted placing and righting reflexes. The non-competitive NMDA antagonist MK-801 also produced evidence of balan ce loss and falling. The data indicate that the doses of EAA antagonis ts which produce significant antinociceptive effects also produce evid ence of motor dysfunction. This suggests that EAA receptor antagonists may have a limited therapeutic range and, therefore, may not be parti cularly useful as analgesic agents for the treatment of clinical pain. Studies in the following article suggest that this problem may be ove rcome by using low-dose combinations of agents acting at various compo nents of the NMDA receptor complex.