∆(9)-Tetrahydrocannabinol, a major marijuana component, enhances the anesthetic effect of pentobarbital through the CB(1) receptor

PURPOSE: ∆(9)-Tetrahydrocannabinol (∆(9)-THC) and cannabidiol (CBD), major psychoactive constituents of marijuana, induce potentiation of pentobarbital-induced sleep in mice. We have elucidated the mechanism of enhancement of the anesthetic effect of pentobarbital by cannabinoids. METHODS: We carried out pharmacological experiment and cannabinoid(1) (CB(1)) receptor binding assay using CB(1) antagonists to clarify whether the CB(1) receptor is involved in the synergism or not. The affinities of cannabinoids for the CB(1) receptor in the mouse brain synaptic membrane were evaluated using a specific CB(1) ligand, [(3)H]CP55940. RESULTS: Although the potentiating effect of ∆(9)-THC on pentobarbital-induced sleep was attenuated by co-administration of CB(1) receptor antagonists, such as SR141716A and AM251, at a dose of 2 mg/kg, intravenously (i.v.) to mice, the CBD-enhanced pentobarbital-induced sleep was not inhibited by SR141716A. The inhibitory constant (Ki) values of ∆(9)-THC and CBD were 6.62 and 2010 nM, respectively, showing a high affinity of ∆(9)-THC and a low affinity of CBD for the CB(1) receptor, respectively. A high concentration of pentobarbital (1 mM) did not affect specific [(3)H]CP55940 binding on the mouse brain synaptic membrane. CONCLUSIONS: These results suggest that binding of ∆(9)-THC to the CB(1) receptor is involved in the synergism with pentobarbital, and that potentiating effect of CBD with pentobarbital may differ from that of ∆(9)-THC. We successfully demonstrated that ∆(9)-THC enhanced the anesthetic effect of pentobarbital through the CB(1) receptor.