Reinforcing effects of opioid/cannabinoid mixtures in rhesus monkeys responding under a food/drug choice procedure
Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ9-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).
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 Δ9-THC (10–100 μg/kg/infusion) or the synthetically derived cannabinoid receptor agonist CP55940 (3.2–10 μg/kg/infusion).
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.
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.
KeywordsOpioids Cannabinoids Drug mixtures Choice procedures Drug self-administration Rhesus monkeys
The authors thank Eli Desarno, Steven Garza, Sarah Howard, Jade Juarez, Krissian Martinez, Emily Spolarich, and Samuel Womack for excellent technical assistance. Special thanks to Drs. Gail Winger and Yonggong Shi for technical assistance. This work was supported by the National Institutes of Health (R01DA005018) and the Welch Foundation (AQ-0039). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Institute on Drug Abuse.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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