Effects of ACEA-1328, a NMDA receptor/glycine site antagonist, on U50,488H-induced antinociception and tolerance

Previously, we have shown that inhibition of the glycine site associated wi th the N-methyl-D-aspartate (NMDA) receptor is another viable approach to b locking morphine tolerance. In the present study, we sought to investigate the involvement of the NMDA receptor/glycine site in kappa-opioid receptor- mediated antinociception and tolerance in CD-1 mice. In antinociception stu dies, mice were injected with 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxal inedione (ACEA-1328), a systemically bioavailable NMDA receptor/glycine sit e antagonist, or the vehicle (Bis-Tris, 0.2 M) and then immediately with tr ans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneac etamide methanesulfonate (U50,488H), a kappa-opioid receptor agonist. Thirt y minutes later, mice were tested for changes in nociceptive responses in t he tail flick assay. ACEA-1328, per se, prolonged tail flick latencies with an ED50 of approximately 50 mg/kg. Concurrent administration of ACEA-1328, at doses that did not produce antinociception, with U50,488H increased the potency of U50,488H in a dose-dependent manner. In tolerance studies, mice were treated, either once a day for 9 days or twice daily for 4 days, with the vehicle or ACEA-1328. Immediately after the initial injection, mice th en received an injection of saline or U50,488H. On the test day, mice were injected with U50,488H alone and tested for antinociception 30 min later. C hronic treatment with U50,488H by either method produced tolerance. Unlike the acute effect of the drug, chronic treatment with ACEA-1328 decreased th e antinociceptive potency of U50,488H. Taken together, the data suggest tha t acute and chronic administration of ACEA-1328 differentially affected the antinociceptive effect of U50,488H. Furthermore, the decreased in the pote ncy of U50,488H induced by chronic treatment with ACEA-1328 also confounded the interpretation of the tolerance data. (C) 1999 Elsevier Science B.V. A ll rights reserved.