Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal
Open accessAbstract
Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not markedly altered by concurrent treatment with THC. Thus, THC can enhance some (antinociception, tolerance) but not all (dependence) effects of morphine.
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Combined administration of morphine and THC produces augmented antinociceptive effects in the rhesus monkey warm water withdrawal test.
“Specifically, combined administration of morphine and THC produces augmented antinociceptive effects in the rhesus monkey warm water withdrawal test (Gerak and France, 2016;Li et al, 2008).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Gerak and France, 2016
In nonhuman primates, the combination of opioids and cannabinoids results in increased antinociceptive tolerance and cross-tolerance to opioids.
“In contrast to work conducted on rodents (Smith et al, 2007), the combination of opioids and cannabinoids results in increased antinociceptive tolerance and cross-tolerance to opioids in nonhuman primates (Gerak and France, 2016), which underscores the importance of testing in higher animals.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Gerak and France, 2016
Opioid-cannabinoid combinations lead to enhanced antinociception in laboratory animal pain models but do not increase untoward side effects of opioids, such as respiratory depression, abuse liability or constipation.
“In summary, opioid-cannabinoid combinations lead to enhanced antinociception in laboratory animal pain models but do not increase untoward side effects of opioids, such as respiratory depression, abuse liability (Gerak and France, 2016) or constipation (Wilkerson et al, 2016b).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Gerak and France, 2016
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- Authors
- Gerak, L. R., & France, C. P.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 357
- Issue
- 2
- Pages
- 357-366
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC4851324
- OpenAlex
- W2289115175
- Cited by
- 26
- References
- 48
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 2
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (R01DA05018, K05 DA17918, K05DA017918, R01DA005018)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- morphine, delta-9-tetrahydrocannabinol, antinociceptive tolerance, opioid use disorder, morphine withdrawal, CP55,940, U50,488, kappa opioid receptor agonists, cannabinoid receptor agonists, analgesic potentiation
- MeSH terms
- Analgesics, Analgesics, Opioid, Animals, Cyclohexanols, Dose-Response Relationship, Drug, Drug Tolerance, Heart Rate, Macaca mulatta, Morphine, Morpholines, Naphthalenes, Opioid-Related Disorders, Pain Measurement, Substance Withdrawal Syndrome, Dronabinol, 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer, Benzoxazines, Cannabinoid Receptor Agonists
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