Opioid and cannabinoid modulation of precipitated withdrawal in δ9-tetrahydrocannabinol and morphine-dependent mice

A. H. Lichtman, S. M. Sheikh, H. H. Loh, B. R. Martin

Research output: Contribution to journalArticlepeer-review

152 Scopus citations


The goal of the present study was to elucidate the relationship between cannabinoid and opioid systems in drug dependence. The CB1 cannabinoid receptor antagonist SR 141716A precipitated both paw tremors and head shakes in four different mouse strains that were treated repeatedly with Δ9-tetrahydrocannabinol (Δ9-THC). SR 141716A-precipitated Δ9-THC withdrawal was ameliorated in μ-opioid receptor knockout mice compared with the wild-type control animals and failed to occur in mice devoid of CB1 cannabinoid receptors. An acute injection of morphine in Δ9-THC-dependent mice undergoing SR 1417161A-precipitated withdrawal dose dependently decreased both paw tremors, antagonist dose 50 (AD50) (95% CL) = 0.035 (0.03-0.04), and head shakes, AD50 (95% CL)= 0.07 (0.04-0.12). In morphine-dependent mice, the opioid antagonist naloxone precipitated head shakes, paw tremors, diarrhea, and jumping. As previously reported, naloxone-precipitated morphine withdrawal failed to occur in μ-opioid knockout mice and was significantly decreased in CB1 cannabinoid receptor knockout mice. Acute treatment of Δ9-THC in morphine-dependent mice undergoing naloxone-precipitated withdrawal blocked paw tremors, AD50, (95% CL) = 0.5 (0.3-1.0), and head shakes AD50 (95% CL) = 0.6 (0.57-0.74) in dose-dependent manners, but failed to diminish the occurrence of diarrhea or jumping. Finally, naloxone and SR 141716A failed to elicit any overt effects in Δ9-THC-dependent and morphine-dependent mice, respectively. These findings taken together indicate that the μ-opioid receptor plays a modulatory role in cannabinoid dependence, thus implicating a reciprocal relationship between the cannabinoid and opioid systems in dependence.

Original languageEnglish (US)
Pages (from-to)1007-1014
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 2001


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