Evidence for a bidirectional cross-tolerance between morphine and Δ 9-tetrahydrocannabinol 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. Δ 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 Δ 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 Δ 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 Δ 9-tetrahydrocannabinol. These results indicate that a possible interaction exists between Δ 9-tetrahydrocannabinol and the μ-opioid receptors and that a substantial tolerance to analgesic and hypothermic effects of morphine develops in Δ 9-tetrahydrocannabinol-tolerant mice. To investigate whether the chronic administration of Δ 9-tetrahydrocannabinol alters the μ-opioid receptors in the central nervous system (CNS), the binding of a selective μ-opioid receptor agonist, [ 3H][ D -Ala 2, MePhe 4, Gly-ol 5]enkephalin ([ 3H]DAMGO), to whole brain and spinal cord μ-opioid receptors was determined in Δ 9-tetrahydrocannabinol-tolerant animals. The B max and K d values of [ 3H]DAMGO in brain or the spinal cord of Δ 9-tetrahydrocannabinol-tolerant mice were not altered. Thus, evidence is presented for the existence of bidirectional cross- tolerance between morphine and Δ 9-tetrahydrocannabinol in the mouse without changes in μ-opioid receptors of the central nervous system.