Interactions between Δ⁹-tetrahydrocannabinol and μ opioid receptor agonists in rhesus monkeys: Discrimination and antinociception

Rationale: Opioid receptor agonists can enhance some effects of cannabinoid receptor agonists, and cannabinoid receptor agonists can enhance some effects of opioid receptor agonists; however, the generality of these interactions is not established. Objective: This study examined interactions between the discriminative stimulus and antinociceptive effects of μ opioid receptor agonists and Δ⁹-tetrahydrocannabinol (THC) in rhesus monkeys. Results: Neither heroin nor morphine (intravenous (i.v.) or subcutaneous (s.c.)) altered the discriminative stimulus effects of THC in monkeys (n=5) discriminating 0.1 mg/kg THC i.v. In contrast, THC (s.c.) markedly attenuated the discriminative stimulus effect of morphine and heroin in nondependent monkeys (n=4) discriminating 1.78 mg/kg morphine s.c. Doses of THC that attenuated the discriminative stimulus effects of morphine in nondependent monkeys failed to modify the discriminative stimulus effects of morphine in morphine-dependent (5.6 mg/kg/12 h) monkeys (n=4) discriminating 0.0178 mg/kg naltrexone s.c. THC also failed to modify the discriminative stimulus effects of naltrexone in morphine-dependent monkeys or the effects of midazolam in monkeys (n=4) discriminating 0.32 mg/kg midazolam s.c. Doses of THC (s.c.) that attenuated the discriminative stimulus effects of morphine in nondependent monkeys enhanced the antinociceptive effects of morphine (s.c.) in nondependent monkeys. While μ receptor agonists did not alter the discriminative stimulus effects of THC, THC altered the effects of μ receptor agonists in a context-dependent manner. Conclusion: That the same doses of THC enhance, attenuate, or do not affect morphine, depending on the condition, suggests that attenuation of morphine by THC can result from perceptual masking rather than common pharmacodynamic mechanisms or pharmacokinetic interactions.