Abstract
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.MethodsWe 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 CB1 ligand, [3H]CP55940.ResultsAlthough 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.ConclusionsThese 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 CB1 receptor.
Highlights
While the current number of people arrested for marijuana (Cannabis sativa L)-related crimes under the Cannabis Control Law in Japan has decreased relatively over the past 10 years, there has been a gradually increase since 2014 [1]
We reveal the involvement of the CB1 receptor for potentiating pentobarbital-induced sleep by ∆9-THC in mice using specific CB1 receptor antagonists
The effects of cannabinoid receptor antagonists on the synergistic effects of pentobarbital with ∆9-THC are shown in Fig. 2. ∆9-THC [vehicle (Veh) + ∆9-THC 10 mg/kg, i.v.] significantly prolonged pentobarbital-induced sleep by 3.3-folds compared with the vehicle-pretreated group (Veh + Veh)
Summary
While the current number of people arrested for marijuana (Cannabis sativa L)-related crimes under the Cannabis Control Law in Japan has decreased relatively over the past 10 years, there has been a gradually increase since 2014 [1]. CBD is known to prolong pentobarbital-induced sleep, but the potentiation mechanism was thought to differ to ∆9-THC. The CB1 receptor affinity of CBD is quite low and pentobarbital-induced sleep-prolonging effects with CBD were due to inhibition of hepatic cytochrome P450 activity [27,28,29,30]. Our previous data show that the pharmacological profile of each cannabinoid, including active metabolites such as 11-hydroxy-∆9-THC and 11-oxo-∆9-THC, based on the effects of hypothermia, catalepsy, and pentobarbital-induced sleep, differ widely in their site of action in the CNS [18,19,20,21,22,23,24,25,26]. We reveal the involvement of the CB1 receptor for potentiating pentobarbital-induced sleep by ∆9-THC in mice using specific CB1 receptor antagonists
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