Biochemical and behavioral studies on the interaction between μ- and κ-opiate agonists in mice

Abstract

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 κ-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 [ 3H]ethylketocyclazocine (EKC) and [ 3H]D-Ala 2,MePhe 4, Gly-ol 5-enkephalin (DAMGO) to whole brain and spinal cord κ- and μ-opiate receptors was determined. Tolerance to U-50,488H was associated with down-regulation of κ-opiate receptors in the spinal cord where the K d value of [ 3H]EKC was increased but the B max value did not change. On the other hand, μ-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 [ 3H]DAMGO but the K d values did not change. Thus, biochemical and behavioral evidence is presented for the existence of cross-tolerance between μ- and κ-opiate agonists in mice.