∆9-Tetrahydrocannabinol, a major marijuana component, enhances the anesthetic effect of pentobarbital through the CB1 receptor

∆ 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. 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. 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. 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.