ACEA-1328, an NMDA receptor antagonist, increases the potency of morphine and U50,488H in the tail flick test in mice

The effect of 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1 328), a competitive and systemically bioavailable NMDA receptor/glycine sit e antagonist, was examined on opioid-induced antinociception in the tail fl ick test. Swiss Webster mice were injected with ACEA-1328 either alone or i n combination with morphine or (+/-)-trans-U50488 methanesulfonate (U50,488 H), a mu- and a kappa-opioid receptor agonist, respectively, and tested for antinociception. Systemic administration of ACEA-1328 alone increased the tail flick latencies with an ED50 of approximately 45 mg kg(-1). Concurrent administration of ACEA-1328 with morphine, or U50,488H, at doses that did not affect tail flick latencies, potentiated the antinociceptive effect of the opioid analgesics and vice versa. Naloxone, an opioid receptor antagoni st, while not modifying the effect of ACEA-1328, did block the augmentation , suggesting that opioid receptors might be involved in the latter effect. 5-Aza-7-chloro-4-hydroxy-3-(m-phenoxyphenyl)quinoline-2(1H)-one (ACEA-0762) , a selective NMDA receptor/glycine site antagonist, also showed enhancemen t of the antinociceptive effect of morphine and U50,488H. However, concurre nt administration of 2,3-dihydroxy-6 -nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX), a selective non-NMDA receptor antagonist, with morphine did not al ter the antinociceptive potency of the opioid analgesic. Overall, the data suggest that ACEA-1328 may increase the potency of the opioid analgesics by antagonising the glycine site associated with the NMDA receptor. (C) 1998 The Italian Pharmacological Society.