Cited by 110Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsPain Management and Opioid Use

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Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral Δ9-Tetrahydrocannabinol

Cichewicz, Diana L., Welch, Sandra P.·2003·The Journal of Pharmacology and Experimental Therapeutics

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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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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)
DOI: 10.1124/jpet.102.046870
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral Δ9-Tetrahydrocannabinol

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