∆9-Tetrahydrocannabinol, a major marijuana component, enhances the anesthetic effect of pentobarbital through the CB1 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 cannabinoid₁ (CB₁) receptor binding assay using CB₁ antagonists to clarify whether the CB₁ receptor is involved in the synergism or not. The affinities of cannabinoids for the CB₁ receptor in the mouse brain synaptic membrane were evaluated using a specific CB₁ligand, [³H]CP55940.

RESULTS:

Although the potentiating effect of ∆⁹-THC on pentobarbital-induced sleep was attenuated by co-administration of CB₁ 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 CB₁ receptor, respectively. A high concentration of pentobarbital (1 mM) did not affect specific [³H]CP55940 binding on the mouse brain synaptic membrane.

CONCLUSIONS:

These results suggest that binding of ∆⁹-THC to the CB₁ 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 CB₁receptor.