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Vol. 298, Issue 3, 1007-1014, September 2001
9-Tetrahydrocannabinol and Morphine-Dependent Mice
Department of Pharmacology and Toxicology, Medical College of
Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
(A.H.L., S.M.S., B.R.M.); and University of Minnesota, Minneapolis,
Minnesota (H.H.L.)
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 
9-tetrahydrocannabinol
(9-THC). SR 141716A-precipitated 9-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 9-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 9-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
9-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.
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