Interactions between μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

Maguire, David R.; Yang, Wenjuan; France, Charles P.

doi:10.1124/jpet.113.204099

Cited by 72Cannabis and Cannabinoid ResearchNeurotransmitter Receptor Influence on BehaviorPain Mechanisms and Treatments

Interactions between μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

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Maguire, David R., Yang, Wenjuan, France, Charles P.·2013·The Journal of Pharmacology and Experimental Therapeutics

DOI 10.1124/jpet.113.204099PMC PMC3657106

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Abstract

Cannabinoid receptor agonists enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combinations of these drugs might enhance therapeutic effectiveness (e.g., analgesia). However, it is not clear whether combinations of these drugs also enhance abuse or dependence liability. This experiment examined whether combinations of cannabinoids and opioids that enhance antinociception also increase abuse-related effects by studying the effects of the cannabinoid receptor agonists 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212) on the antinociceptive, discriminative stimulus, and positive reinforcing effects of μ-opioid receptor agonists in rhesus monkeys. In one group of monkeys (n = 3), morphine (0.1-5.6 mg/kg s.c.), CP 55,940 (0.0032-0.032 mg/kg s.c.), and WIN 55,212 (0.1-1.0 mg/kg s.c.) dose-dependently increased tail withdrawal latency from 50°C water, and pretreatment with small, otherwise ineffective, doses of CP 55,940 and WIN 55,212 shifted the morphine dose-effect curve to the left. In monkeys (n = 3) discriminating 3.2 mg/kg morphine, CP 55,940 (0.01-0.032 mg/kg s.c.) and WIN 55,212 (0.1-1.78 mg/kg s.c.) attenuated the discriminative stimulus effects of morphine, shifting the dose-effect curve to the right. In monkeys (n = 4) self-administering heroin (0.32-32.0 µg/kg/infusion i.v.), CP 55,940 (0.001-0.032 mg/kg s.c.), and WIN 55,212 (0.1-1.0 mg/kg s.c.) shifted the heroin dose-effect curve rightward and downward. Cannabinoid receptor agonists CP 55,940 and WIN 55,212 enhanced the antinociceptive effects but not the discriminative stimulus or positive reinforcing effects of μ-opioid receptor agonists in rhesus monkeys, supporting the view that combining cannabinoid and opioid receptor agonists might result in enhanced treatment effectiveness for pain without similarly enhancing abuse and dependence liability.

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Subthreshold doses of either CP55,940 or WIN55212-2 produce leftward shifts of the morphine dose-response curve in the rhesus monkey warm water withdrawal assay.
“Subthreshold doses of either CP55,940 or WIN55212-2 produce leftward shifts of the morphine dose-response curve in this assay, but elicit rightward and downward shifts of the morphine dose response curves in the drug discrimination and selfadministration assays (Maguire et al, 2013), suggesting decreased abuse liability.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Maguire et al, 2013
Subthreshold doses of CP55,940 or WIN55212-2 elicit rightward and downward shifts of the morphine dose-response curves in drug discrimination and self-administration assays.
“Subthreshold doses of either CP55,940 or WIN55212-2 produce leftward shifts of the morphine dose-response curve in this assay, but elicit rightward and downward shifts of the morphine dose response curves in the drug discrimination and selfadministration assays (Maguire et al, 2013), suggesting decreased abuse liability.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Maguire et al, 2013

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Authors: Maguire, D. R., Yang, W., & France, C. P.
Affiliations: The University of Texas at San Antonio Health Science Center (US)
ORCID: Maguire, David R.
Yang, Wenjuan
Venue: The Journal of Pharmacology and Experimental Therapeutics
Publisher: Elsevier BV
Published: 2013-06
Volume: 345
Issue: 3
Pages: 354-362
ISSN: 0022-3565 (ISSN-L)
DOI: 10.1124/jpet.113.204099
PMC: PMC3657106
OpenAlex: W2132271948
Cited by: 71
References: 48
Citations by year: 2026: 2 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 6 · 2016: 7 · 2015: 7 · 2014: 4
FWCI: 4.41
Type: journal article
Language: en
Update notices: erratum (2014-03-01)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Drug Abuse (K05 DA17918, K05DA017918, T32DA031115, R01DA005018)
Topics: Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Keywords: mu-opioid receptor agonists, cannabinoid receptor agonists, drug interactions, antinociception, morphine, heroin, CP55,940, drug discrimination, self-administration, abuse liability, dependence liability, analgesia, rhesus monkeys, tail withdrawal latency, discriminative stimulus, positive reinforcement
MeSH terms: Analgesics, Analgesics, Opioid, Animals, Cyclohexanols, Data Interpretation, Statistical, Discrimination, Psychological, Dose-Response Relationship, Drug, Hot Temperature, Heroin Dependence, Macaca mulatta, Morphine, Morpholines, Naphthalenes, Pain Measurement, Self Administration, Dronabinol, Receptors, Opioid, mu, Receptors, Cannabinoid, Benzoxazines, Cannabinoid Receptor Agonists

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Interactions between μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

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