BIOCHEMICAL AND BEHAVIORAL-STUDIES ON THE INTERACTION BETWEEN MU-OPIATE AND KAPPA-OPIATE AGONISTS IN MICE

Male Swiss-Webster mice were rendered tolerant to morphine by subcutaneous implantation of a morphine pellet, each containing 75 mg morphine base, for 3 days. Mice implanted with placebo pellets served as controls. A high degree of tolerance to the analgesic effect of morphine developed as evidenced by decreased analgesic response to various doses of morphine, A selective kappa-opiate agonist, U-50,488H (8, 16 and 32 mg/kg, i.p.) produced dose-dependent analgesic and hypothermic effects in mice implanted with placebo pellets. A significant decrease in the analgesic and hypothermic effects of U-50,488H was observed in morphine tolerant mice as compared to placebo-treated mice. Mice were rendered tolerant to U-50,488H by injecting the drug (25 mg/kg, i.p.) twice daily for 4 days. Vehicle injected mice served as controls. Tolerance to the analgesic and hypothermic effects of U-50,488H in mice injected chronically with the drug was evidenced by the decreases in the intensity of these responses when compared to those observed in vehicle injected controls. Morphine produced a dose-dependent analgesic and hypothermic effects in mice injected chronically with vehicle but the intensity of these effects was significantly lower in mice injected chronically with U-50,488H. These results indicate that a substantial tolerance to analgesic and hypothermic effects of U-50,488H develops in morphine tolerant mice. The effect of chronic injections of U-50,488H on the binding of [H-3]ethylketocyclazocine (EKC) and [H-3]D-Ala2,MePhe4,Gly-ol5-enkephalin (DAMGO) to whole brain and spinal cord kappa- and mu-opiate receptors was determined. Tolerance to U-50,488H was associated with down-regulation Of kappa-Opiate receptors in the spinal cord where the K(d) value of [H-3]EKC was increased but the B(max) value did not change. On the other hand, mu-opiate receptors were increased in the brain but were decreased in the spinal cord. In both cases the changes in binding were due to alterations in the B(max) values of [H-3]DAMGO but the K(d) values did not change. Thus, biochemical and behavioral evidence is presented for the existence of cross-tolerance between mu- and kappa-opiate agonists in mice.