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.