Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice

Eur J Pharmacol. 1994 Jul 21;260(1):5-13. doi: 10.1016/0014-2999(94)90003-5.


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)

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Body Temperature / drug effects
  • Brain / metabolism
  • Dose-Response Relationship, Drug
  • Dronabinol / administration & dosage
  • Dronabinol / pharmacology*
  • Drug Implants
  • Drug Tolerance
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalins / pharmacokinetics
  • Enkephalins / pharmacology
  • In Vitro Techniques
  • Male
  • Membranes / drug effects
  • Membranes / metabolism
  • Mice
  • Morphine / administration & dosage
  • Morphine / pharmacology*
  • Pain Measurement / drug effects
  • Receptors, Opioid, mu / drug effects
  • Spinal Cord / metabolism


  • Analgesics
  • Drug Implants
  • Enkephalins
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Morphine
  • Dronabinol