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

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.