The effects of delta1-tetrahydrocannabinol and other cannabinoids on spin-labeled liposomes and their relationship to mechanisms of general anesthesia.

Abstract

The effects of (-)- and (+)-Δ 1 -tetrahydrocannabinol (Δ 1 -THC), the dimethylheptyl analogue of (-)-Δ 1 -THC, 7-hydroxy-Δ 1 -THC, cannabinol, and cannabidiol on the molecular mobility of the hydrocarbon phase of lecithin/cholesterol ultrasonically dispersed vesicles (liposomes) were investigated using a nitroxide-labeled dipalmitoyllecithin as a molecular probe. At low concentrations (-)-Δ 1 -THC fluidized the lipid bilayer; at Δ 1 -THC to lecithin ratios greater than 0.05:1 the effect leveled off and the change in the order parameter remained constant and independent of the membrane concentration. The maximum increase in bilayer fluidity produced by Δ 1 -THC was considerably less than that produced by general anesthetics at membrane concentrations corresponding to those producing anesthesia in vivo . (+)-Δ 1 -THC (the unnatural optical isomer of Δ 1 -THC) was less effective than (-)-Δ 1 -THC, whereas the dimethylheptyl analogue and 7-hydroxy-Δ 1 -THC were more effective. Hence ability, at low concentrations, to disorder liposome bilayers correlates well with psychoactive potency. Cannabinol and cannabidiol decreased the fluidity of the liposome bilayer. Octanol, a potent general anesthetic, fluidized lipid bilayers; hexadecanol and tetradecane (which do not produce anesthesia in vivo ) were less effective than Δ 1 -THC in fluidizing liposomes and, at high doses, produced a cannabis-like cataleptic state in mice. It is suggested that the psychoactive cannabinoids may be classified as partial producing a perturbation of the membrane structure qualitatively similar to that produced by subanesthetic doses of general anesthetics, but which, because of their limited solubility in the lipid phase of cell membranes, are unable to produce the degree of membrane disorder corresponding to clinical anesthesia.