BLOCKADE OF MU-OPIOID AND KAPPA(1)-OPIOID ANALGESIC TOLERANCE BY NPC17742, A NOVEL NMDA ANTAGONIST

NPC17742 is a potent competitive NMDA antagonist. Low doses of NPC1774 2 prevent the development of tolerance to repeated daily injections of the mu agonist morphine and the kappa1 agonist U50,488H. However, NPC 17742 at these same doses is without effect against the kappa3 analges ic 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 bloc k tolerance to U50488H distinguishes this compound from other NMDA ant agonists and raises the possibility of subclasses of NMDA antagonists. Furthermore, these results emphasize the different mechanisms involve d with analgesic tolerance among mu, kappa1 and kappa3 receptors.