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Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral Δ9-Tetrahydrocannabinol
Abstract
Previous studies have demonstrated a functional interaction between cannabinoid and opioid systems in the development and expression of morphine tolerance and dependence. In these experiments, we examined the effect of a low oral dose of Delta 9-tetrahydrocannabinol (Delta 9-THC) on the development of oral morphine tolerance and the expression of naloxone-precipitated morphine withdrawal signs of jumping and diarrhea in ICR mice. Chronic treatment with high-dose oral morphine produced a 3.12-fold antinociceptive tolerance. Tolerance to morphine was prevented in groups receiving a daily cotreatment with a nonanalgetic dose (20 mg/kg p.o.) of Delta 9-THC, except when challenged with a very high dose of morphine. The chronic coadministration of low-dose Delta 9-THC also reduced naloxone-precipitated (1 mg/kg s.c.) platform jumping by 50% but did not reduce diarrhea. In separate experiments, mice treated chronically with high-dose morphine p.o. were not cross-tolerant to Delta 9-THC; in fact, these morphine-tolerant mice were more sensitive to the acute antinociceptive effects of Delta 9-THC. Delta 9-THC (20 mg/kg p.o.) also reduced naloxone-precipitated jumping but not diarrhea when administered acutely to morphine-tolerant mice. These results represent the first evidence that oral morphine tolerance and dependence can be circumvented by coadministration of a nonanalgetic dose of Delta 9-THC p.o. In summary, cotreatment with a combination of morphine and Delta 9-THC may prove clinically beneficial in that long-term morphine efficacy is maintained.
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“Further, administration of a low dose of THC in combination with morphine prevents tolerance to morphine in the tail flick assay for acute pain (Cichewicz and Welch, 2003).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Cichewicz and Welch, 2003
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A METHOD FOR DETERMINING LOSS OF PAIN SENSATION
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Cellular and Synaptic Adaptations Mediating Opioid Dependence
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SIMULTANEOUS QUANTITATIVE ASSESSMENT OF MORPHINE TOLERANCE AND PHYSICAL DEPENDENCE
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Functional Dissociation of μ Opioid Receptor Signaling and Endocytosis
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Regulation of Opioid Receptor Trafficking and Morphine Tolerance by Receptor Oligomerization
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- Ellison NM (1993) Opioid analgesics for cancer pain: toxicities and their treatments, in Cancer Pain (Patt RB ed) pp 185–194, JB Lippincott, Philadelphia.
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The Endocannabinoid System’s Contribution to Placebo AnalgesiaPreprint
Tomin, R., Murray, K., Hadjis, G. E., Khalil, O., Sexton, C. A., Bourke, S. L., Khan, J. S., Finn, D. P., Atlas, L. Y., & Moayedi, M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.25.707676
Mohammadkhani, A., Peterson, C. S., & Borgland, S. L. (2026) · Springer eBooks · doi:10.1007/978-3-032-12239-1_14
BindingDB (2021) · UC San Diego · doi:10.7270/q2z60sd8
Metadata
- Authors
- Cichewicz, D. L., & Welch, S. P.
- Affiliations
- Virginia Commonwealth University (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 305
- Issue
- 3
- Pages
- 812-817
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2138954299
- Cited by
- 110
- References
- 43
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 5 · 2016: 6 · 2015: 5 · 2014: 4 · 2013: 5 · 2012: 10
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k02da000186-09)
- National Institute on Drug Abuse (DA 07027, DA 05274, K02 DA-00186, T32DA007027)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- morphine tolerance, naloxone-precipitated withdrawal, delta-9-tetrahydrocannabinol, opioid-cannabinoid interaction, opioid use disorder, antinociception, diarrhea, cross-tolerance, chronic morphine administration, oral administration
- MeSH terms
- Administration, Oral, Analgesics, Analgesics, Opioid, Animals, Dose-Response Relationship, Drug, Drug Tolerance, Hallucinogens, Male, Mice, Inbred ICR, Morphine, Morphine Dependence, Naloxone, Narcotic Antagonists, Substance Withdrawal Syndrome, Dronabinol, Mice
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