EVIDENCE FOR A BIDIRECTIONAL CROSS-TOLERANCE BETWEEN MORPHINE AND DELTA(9)-TETRAHYDROCANNABINOL 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. Delta(9)-Tetrahydrocannabinol (5, 10 and 20 mg/kg i.p.) produced dose-dependent analgesic and hypothermic effects in mice implanted with placebo pellets. A significant decrease in the analgesic effects of tetrahydrocannabinol was observed in morphine-tolerant mice as compared to placebo controls. Mice were rendered tolerant to Delta(9)-tetrahydrocannabinol by injecting the drug (5, 10, or 20 mg/kg i.p.) twice daily for 4 days. Vehicle-injected mice served as controls. Tolerance to the analgesic and hypothermic effects of Delta(9)-tetrahydrocannabinol 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 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 Delta(9)-tetrahydrocannabinol. These results indicate that a possible interaction exists between Delta(9)-tetrahydrocannabinol and the mu-opioid receptors and that a substantial tolerance to analgesic and hypothermic effects of morphine develops in Delta(9)-tetrahydrocannabinol-tolerant mice. To investigate whether the chronic administration of Delta(9)-tetrahydrocannabinol alters the mu-opioid receptors in the central nervous system (CNS), the binding of a selective mu-opioid receptor agonist, [(3H)][D-Ala(2),MePhe(4),Gly-ol(5)]enkephalin ([H-3]DAMGO), to whole brain and spinal cord mu-opioid receptors was determined in Delta(9)-tetrahydrocannabinol-tolerant animals. The B-max and K-d values of [3H]DAMGO in brain or the spinal cord of Delta(9)-tetrahydrocannabinol-tolerant mice were not altered. Thus, evidence is presented for the existence of bidirectional cross-tolerance between morphine and Delta(9)-tetrahydrocannabinol in the mouse without changes in mu-opioid receptors of the central nervous system.