NONCOMPETITIVE ANTAGONISM OF N-METHYL-D-ASPARTATE RECEPTOR INHIBITS TOLERANCE TO THE ANALGESIC ACTION OF U-50,488H, A KAPPA-OPIATE RECEPTOR AGONIST IN THE RAT

1. The effect of dizocilpine (MK-801), a non-competitive inhibitor of N-methyl-D-aspartate (NMDA) receptor on the development of tolerance to the analgesic and hypothermic actions of U-50,488H, a highly selective kappa-opiate receptor agonist, was determined-in the rat. 2. Male Sprague-Dawley rats were made tolerant to the pharmacological actions of U 50,488H by twice daily intraperitoneal (i.p.) injections of the drug (25 mg/kg) for 4 days. 3. Multiple injections of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic actions in the rat. MK-801 injected 10 min before each injection of U-50,488H, dose-dependently inhibited the development of tolerance to the analgesic action but the tolerance to the hypothermic action of U-50,488H was unaffected. 4. Multiple injections of U-50,488H decreased the body weight gain. MK-801 dose-dependently decreased the gain in body weight further. 5. The results indicate that non-competitive antagonism of the NMDA receptor by MK-801 can selectively inhibit the tolerance to the analgesic action of U-50,488H in the rat, however, such an effect was associated with significant decreases in normal gain in body weight.