Reinforcing effects of opioid/cannabinoid mixtures in rhesus monkeys responding under a food/drug choice procedure

Objective: Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ ⁹ -THC) enhance the antinociceptive potency of mu opioid receptor agonists such as morphine, indicating that opioid/cannabinoid mixtures might be effective for treating pain. However, such enhancement will be beneficial only if cannabinoids do not also enhance adverse effects of opioids, including those related to abuse. In rhesus monkeys, cannabinoids fail to enhance and often decrease self-administration of the mu opioid receptor agonist heroin, suggesting that opioid/cannabinoid mixtures do not have greater reinforcing effects (abuse potential) compared with opioids alone. Previous studies on the self-administration of opioid/cannabinoid mixtures used single-response procedures, which do not easily differentiate changes in reinforcing effects from other effects (e.g., rate decreasing). Methods: In this study, rhesus monkeys (n = 4) responded under a choice procedure wherein responding on one lever delivered sucrose pellets and responding on the other lever delivered intravenous infusions of the mu opioid receptor agonist remifentanil (0.032–1.0 μg/kg/infusion) alone or in combination with either Δ ⁹ -THC (10–100 μg/kg/infusion) or the synthetically derived cannabinoid receptor agonist CP55940 (3.2–10 μg/kg/infusion). Results: Remifentanil dose-dependently increased choice of drug over food, whether available alone or in combination with a cannabinoid, and the potency of remifentanil was not significantly altered by coadministration with a cannabinoid. Mixtures containing the largest doses of cannabinoids decreased response rates in most subjects, confirming that behaviorally active doses were studied. Conclusion: Overall, these results extend previous studies to include choice behavior and show that cannabinoids do not substantially enhance the reinforcing effects of mu opioid receptor agonists.