Abstract
Previous studies have demonstrated a functional interaction between cannabinoid and opioid systems in the development and expression of morphine tolerance and dependence. In these experiments, we examined the effect of a low oral dose of Δ9-tetrahydrocannabinol (Δ9-THC) on the development of oral morphine tolerance and the expression of naloxone-precipitated morphine withdrawal signs of jumping and diarrhea in ICR mice. Chronic treatment with high-dose oral morphine produced a 3.12-fold antinociceptive tolerance. Tolerance to morphine was prevented in groups receiving a daily cotreatment with a nonanalgetic dose (20 mg/kg p.o.) of Δ9-THC, except when challenged with a very high dose of morphine. The chronic coadministration of low-dose Δ9-THC also reduced naloxone-precipitated (1 mg/kg s.c.) platform jumping by 50% but did not reduce diarrhea. In separate experiments, mice treated chronically with high-dose morphine p.o. were not cross-tolerant to Δ9-THC; in fact, these morphine-tolerant mice were more sensitive to the acute antinociceptive effects of Δ9-THC. Δ9-THC (20 mg/kg p.o.) also reduced naloxone-precipitated jumping but not diarrhea when administered acutely to morphine-tolerant mice. These results represent the first evidence that oral morphine tolerance and dependence can be circumvented by coadministration of a nonanalgetic dose of Δ9-THC p.o. In summary, cotreatment with a combination of morphine and Δ9-THC may prove clinically beneficial in that long-term morphine efficacy is maintained.
Footnotes
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This work was supported by National Institute on Drug Abuse Grants DA-07027, DA-05274, and K02-DA-00186.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.046870.
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ABBREVIATIONS: Δ9-THC, Δ9-tetrahydrocannabinol; SR 141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride; % MPE, percentage of maximum possible effect; CL, confidence limits; ANOVA, analysis of variance; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; NMDA, N-methyl-d-aspartate; MK-801, dizocilpine maleate.
- Received November 21, 2002.
- Accepted February 3, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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