Stereospecific presynaptic inhibitory effect of Δ9-tetrahydrocannabinol on cholinergic transmission in the myenteric plexus of the guinea pig

Abstract

Δ9-Tetrahydrocannabinol (THC) is very lipid soluble, as are many anesthetic agents. The action of anesthetics is nonspecific; isomers are equieffective. THC is optically active; therefore, the effects of its stereoisomers were studied on the electrically and chemically stimulated longitudinal muscle strip of guinea pig ileum. The results demonstrate that both isomers depress the response to electrical stimulation in a dose-related manner. The maximum effect is gradually reached in approximately 20 min. The (−) isomer is 24.6-fold more active than the (+) isomer (ED50 for (−) THC is 1.25 × 10−7 M, for (+) THC, 3.08 × 10−6 M) and the site of action appears to be presynaptic because responses to ACh are not significantly depressed. The depressant effects are relatively nonreversible. Membrane concentrations calculated at the ED50 values for the (−) isomer are of the order of 0.5 mM/kg dry membrane, well within the range for anesthesia. Thus THC may be regarded as a partial anesthetic since some of its actions are similar to those of the classical anesthetics, yet it possesses selective action at the neuronal membrane or tissue level.