Opioid and Cannabinoid Modulation of Precipitated Withdrawal in #DELTA#~9-Tetrahydrocannabinol and Morphine-Dependent Mice

摘要

The goal of the present study was to elucidate the relationship between cannabinoid and opioid systems in drug dependence. The CB_1 cannabinoid receptor antagonist SR 141716A precipitated both paw tremors and head shakes in four different mouse strains that were treated repeatedly with #DELTA#~9-tetrahydrocannabinol (#DELTA#~9-THC). SR 141716A-precipitated #DELTA#~9-THC withdrawal was ameliorated in #mu#-opioid receptor knockout mice compared with the wild-type control animals and failed to occur in mice devoid of CB_1 cannabinoid receptors. An acute injection of morphine in #DELTA#~9-THC-dependent mice undergoing SR 141716 A-precipitated withdrawal dose dependently decreased both paw tremors, antagonist does 50 (AD_(50))(95% CL) = 0.035 (0.03-0.04), and head shakes, AD_(50) (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 #mu#-opioid knockout mice and was significantly decreased in CB_1 cannabinoid receptor knockout mice. Acute treatment of #DELTA#~9-THC in morphinedependent mice undergoing naloxone-precipitated withdrawal blocked paw tremors, AD_(50) (95% CL) = 0.5 (0.3-1.0), and head shakes AD_(50) (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 #DELTA#~9-THC-dependent and morphine-dependent mice, respectively. These findings taken together indicate that the #mu#-opioid receptor plays a modulatory role in cannabinoid dependence, thus implicating a reciprocal relationship between the cannabinoid and opioid systems in dependence.