NPC17742 is a potent competitive NMDA antagonist. Low doses of NPC17742 prevent the development of tolerance to repeated daily injections of the mu agonist morphine and the kappa 1 agonist U50,488H. However, NPC17742 at these same doses is without effect against the kappa 3 analgesic naloxone benzoylhydrazone (NalBzoH). At these doses, NPC17742 does not significantly influence morphine's ED50 value following single or repeated doses of the NMDA antagonist. The ability of NPC17742 to block tolerance to U50488H distinguishes this compound from other NMDA antagonists and raises the possibility of subclasses of NMDA antagonists. Furthermore, these results emphasize the different mechanisms involved with analgesic tolerance among mu, kappa 1 and kappa 3 receptors.