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.(ABSTRACT TRUNCATED AT 250 WORDS)
Thorat
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SN
Department of Pharmaceutics and Pharmacodynamics, University of Illinois at Chicago 60612.
Bhargava
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HN
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D004343:Drug Implants; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism
D000700:Analgesics; D004343:Drug Implants; D004745:Enkephalins; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D013759:Dronabinol