EFFECT OF DIZOCILPINE (MK-801) ON ANALGESIA AND TOLERANCE INDUCED BY U-50,488H, A KAPPA-OPIOID RECEPTOR AGONIST, IN THE MOUSE

The effect of dizocilpine (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, on the analgesic response to U-50,488H, a kappa-opioid receptor agonist, and tolerance to the analgesic effect of U-50,488H was determined in mice. The doses of MK-801 used were 0.03-0.30 mg/kg, whereas U-50,488H was administered at a dose of 25 mg/kg. Intraperitoneal (i.p.) administration of U-50,488H (25 mg/kg) produced analgesia as evidenced by the delay in the tail-flick latency in the mouse and lasted for a period of 240 min. MK-801 (0.03-0.30 mg/kg, i.p.) given 30 min prior to the injection of U-50,488H did not modify U-50,488H-induced analgesia. Twice daily administration of U-50,488H (25 mg/kg) for 9 days produced tolerance to its analgesic action. Administration of MK-801 (0.03 and 0.10 mg/kg) injected 30 min before each injection of U-50,488H prevented the development of tolerance to its analgesic effect. The higher dose, 0.3 mg/kg, of MK-801 had a minimal effect on U-50,488H tolerance, It is concluded that MK-801 in doses which do not affect U-50,488H-induced analgesia blocks the development of tolerance to its analgesic action in mice. These studies suggest that NMDA receptors play a crucial role in the development of tolerance to K-opioid agonist in mice.