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Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors.
Eur J Pharmacol. 2007 Oct 01; 571(2-3):129-37.EJ

Abstract

Morphine and delta9-tetrahydrocannabinol (THC) produce antinociception via mu opioid and cannabinoid CB1 receptors, respectively, located in central nervous system (CNS) regions including periaqueductal gray and spinal cord. Chronic treatment with morphine or THC produces antinociceptive tolerance and cellular adaptations that include receptor desensitization. Previous studies have shown that administration of combined sub-analgesic doses of THC+morphine produced antinociception in the absence of tolerance. The present study assessed receptor-mediated G-protein activity in spinal cord and periaqueductal gray following chronic administration of THC, morphine or low dose combination. Rats received morphine (escalating doses from 1 to 6x75 mg s.c. pellets or s.c. injection of 100 to 200 mg/kg twice daily), THC (4 mg/kg i.p. twice daily) or low dose combination (0.75 mg/kg each morphine (s.c) and THC (i.p.) twice daily) for 6.5 days. Antinociception was measured in one cohort of rats using the paw pressure test, and a second cohort was assessed for agonist-stimulated [35S]GTPgammaS binding. Chronic administration of morphine or THC produced antinociceptive tolerance to the respective drugs, whereas combination treatment did not produce tolerance. Administration of THC attenuated cannabinoid CB1 receptor-stimulated G-protein activity in both periaqueductal gray and spinal cord, and administration of morphine decreased mu opioid receptor-stimulated [35S]GTPgammaS binding in spinal cord or periaqueductal gray, depending on route of administration. In contrast, combination treatment did not alter cannabinoid CB1 receptor- or mu opioid receptor-stimulated G-protein activity in either region. These results demonstrate that low dose THC-morphine combination treatment produces antinociception in the absence of tolerance or attenuation of receptor activity.

Authors+Show Affiliations

Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University Medical College of Virginia, Richmond, VA 23298, United States.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17603035

Citation

Smith, Paul A., et al. "Low Dose Combination of Morphine and Delta9-tetrahydrocannabinol Circumvents Antinociceptive Tolerance and Apparent Desensitization of Receptors." European Journal of Pharmacology, vol. 571, no. 2-3, 2007, pp. 129-37.
Smith PA, Selley DE, Sim-Selley LJ, et al. Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur J Pharmacol. 2007;571(2-3):129-37.
Smith, P. A., Selley, D. E., Sim-Selley, L. J., & Welch, S. P. (2007). Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. European Journal of Pharmacology, 571(2-3), 129-37.
Smith PA, et al. Low Dose Combination of Morphine and Delta9-tetrahydrocannabinol Circumvents Antinociceptive Tolerance and Apparent Desensitization of Receptors. Eur J Pharmacol. 2007 Oct 1;571(2-3):129-37. PubMed PMID: 17603035.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. AU - Smith,Paul A, AU - Selley,Dana E, AU - Sim-Selley,Laura J, AU - Welch,Sandra P, Y1 - 2007/06/12/ PY - 2006/09/19/received PY - 2007/05/23/revised PY - 2007/06/04/accepted PY - 2007/7/3/pubmed PY - 2007/10/27/medline PY - 2007/7/3/entrez SP - 129 EP - 37 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 571 IS - 2-3 N2 - Morphine and delta9-tetrahydrocannabinol (THC) produce antinociception via mu opioid and cannabinoid CB1 receptors, respectively, located in central nervous system (CNS) regions including periaqueductal gray and spinal cord. Chronic treatment with morphine or THC produces antinociceptive tolerance and cellular adaptations that include receptor desensitization. Previous studies have shown that administration of combined sub-analgesic doses of THC+morphine produced antinociception in the absence of tolerance. The present study assessed receptor-mediated G-protein activity in spinal cord and periaqueductal gray following chronic administration of THC, morphine or low dose combination. Rats received morphine (escalating doses from 1 to 6x75 mg s.c. pellets or s.c. injection of 100 to 200 mg/kg twice daily), THC (4 mg/kg i.p. twice daily) or low dose combination (0.75 mg/kg each morphine (s.c) and THC (i.p.) twice daily) for 6.5 days. Antinociception was measured in one cohort of rats using the paw pressure test, and a second cohort was assessed for agonist-stimulated [35S]GTPgammaS binding. Chronic administration of morphine or THC produced antinociceptive tolerance to the respective drugs, whereas combination treatment did not produce tolerance. Administration of THC attenuated cannabinoid CB1 receptor-stimulated G-protein activity in both periaqueductal gray and spinal cord, and administration of morphine decreased mu opioid receptor-stimulated [35S]GTPgammaS binding in spinal cord or periaqueductal gray, depending on route of administration. In contrast, combination treatment did not alter cannabinoid CB1 receptor- or mu opioid receptor-stimulated G-protein activity in either region. These results demonstrate that low dose THC-morphine combination treatment produces antinociception in the absence of tolerance or attenuation of receptor activity. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17603035/Low_dose_combination_of_morphine_and_delta9_tetrahydrocannabinol_circumvents_antinociceptive_tolerance_and_apparent_desensitization_of_receptors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)00657-7 DB - PRIME DP - Unbound Medicine ER -