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.
- Bradford AC, Bradford WD, Abraham A, Bagwell Adams G (2018) Association between US state medical cannabis laws and opioid prescribing in the Medicare part D population. JAMA Intern Med. 178:667-672. https://doi.org/10.1001/jamainternmed.2018.0266
- Catania AC (1966) Concurrent operants. In: Honig WK (ed) Operant behavior: areas of research and application, Appleton-Century-Crofts, New York, pp 213–270Google Scholar
- Cooper ZD, Bedi G, Ramesh D, Balter R, Comer SD, Haney M (2018) Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. Neuropsychopharmacology. https://doi.org/10.1038/s41386-018-0011-2 [Epub ahead of print]
- Hruba L, McMahon LR (2014) The cannabinoid agonist HU-210: Pseudo-irreversible discriminative stimulus effects in rhesus monkeys. Eur J Pharmacol 727:35-42. https://doi.org/10.1016/j.ejphar.2014.01.041
- Katz JL (1989) Drugs as reinforcers: pharmacological and behavioural factors. In: JM Liebman JM, Cooper SJ (eds) The Neuropharmacological basis of reward. Oxford University Press, Oxford, pp 164–213Google Scholar
- Li JX, McMahon LR, Gerak LR, Becker GL, France CP (2008) Interactions between Δ 9-tetrahydrocannabinol and μ opioid receptor agonists in rhesus monkeys: discrimination and antinociception. Psychopharmacology 199:199–208. https://doi.org/10.1007/s00213-008-1157-0 CrossRefPubMedPubMedCentralGoogle Scholar
- Maguire DR, Yang W, France CP (2013b) Interactions between μ-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. J Pharmacol Exp Ther 345:354–362. https://doi.org/10.1124/jpet.113.204099 CrossRefPubMedPubMedCentralGoogle Scholar
- National Research Council (2011). Guide for the care and use of laboratory animals, 8th ed. National Academies Press, Washington, D.C.Google Scholar
- Nielsen S, Sabioni P, Trigo JM, Ware MA, Betz-Stablein BD, Murnion B, Lintzeris N, Khor KE, Farrell M, Smith A, Le Foll B (2017) Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology 42:1752–1765. https://doi.org/10.1038/npp.2017.51 CrossRefPubMedPubMedCentralGoogle Scholar
- Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1980) Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther 28:409–416. https://doi.org/10.1038/clpt.1980.181 CrossRefPubMedGoogle Scholar
- Podlesnik CA, Ko MC, Winger G, Wichmann J, Prinssen EP, Woods JH (2011) The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys. Psychopharmacology 213:53–60. https://doi.org/10.1007/s00213-010-2012-7 CrossRefPubMedGoogle Scholar
- Stevenson GW, Folk JE, Rice KC, Negus SS (2005) Interactions between δ and μ opioid agonists in assays of schedule-controlled responding, thermal nociception, drug self-administration, and drug versus food choice in rhesus monkeys: studies with SNC80 [(+)-4-[(αR)-α-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide] and heroin. J Pharmacol Exp Ther 314:221–231. https://doi.org/10.1124/jpet.104.082685 CrossRefPubMedGoogle Scholar