Opioid and cannabinoid modulation of precipitated withdrawal in Delta(9)-tetrahydrocannabinol and morphine-dependent mice

The goal of the present study was to elucidate the relationship between can nabinoid and opioid systems in drug dependence. The CB1 cannabinoid recepto r antagonist SIR 141716A precipitated both paw tremors and head shakes in f our different mouse strains that were treated repeatedly with Delta (9)-tet rahydrocannabinol (Delta (9)-THC). SR 141716A-precipitated Delta (9)-THC wi thdrawal was ameliorated in mu -opioid receptor knockout mice compared with the wild-type control animals and failed to occur in mice devoid of CB1 ca nnabinoid receptors. An acute injection of morphine in Delta (9)-THC-depend ent mice undergoing SR 1417161A-precipitated withdrawal dose dependently de creased both paw tremors, antagonist dose 50 (AD(50)) (95% CL) = 0.035 (0.0 3-0.04), and head shakes, AD(50) (95% CL) = 0.07 (0.04-0.12). In morphine-d ependent mice, the opioid antagonist naloxone precipitated head shakes, paw tremors, diarrhea, and jumping. As previously reported, naloxone-precipita ted morphine withdrawal failed to occur in mu -opioid knockout mice and was significantly decreased in CB1 cannabinoid receptor knockout mice. Acute t reatment of Delta (9)-THC in morphine-dependent mice undergoing naloxone-pr ecipitated 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 manner s, but failed to diminish the occurrence of diarrhea or jumping. Finally, n aloxone and SIR 141716A failed to elicit any overt effects in Ag-THC-depend ent and morphine-dependent mice, respectively. These findings taken togethe r indicate that the mu -opioid receptor plays a modulatory role in cannabin oid dependence, thus implicating a reciprocal relationship between the cann abinoid and opioid systems in dependence.