Cannabinoid Receptor Agonists Inhibit Ca2+ Influx To Synaptosomes From Rat Brain

We examined the effects of cannabinoid receptor agonists on Ca-45(2+) uptake in rat brain synaptosomes. A cannabinoid receptor agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-merpholino)methyl]pyrrolo-[1,2,3-de]-1,4- benzoxazin-6-y](1-naphthyl)methanone (WIN 55212-2) dose-dependently inhibited Ca-45(2+) uptake in rat synaptosomes. Only an endogenous cannabinoid receptor agonist, anandamide, dose-dependently inhibited Ca-45(2+) uptake in rat synaptosomes, but not an endogenous cannabinoid receptor agonist, palmitoylethanolamide. Only a cannabinoid CB1 antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride] (SR 141716A), reversed the inhibitory effect of these WIN 55212-2 and anandamide on Ca-45(2+) uptake in rat synaptosomes, but not a cannabinoid CB2 receptor antagonist, [N-[(1S)endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4- chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3- carboxamide] (SR 144528). The inhibitory effects of WIN 55212-2 and anandamide on Ca-45(2+) uptake in rat synaptosomes were reversed by the pretreatment of a voltage-sensitive A-type K+ channel blocker, dendrotoxin, but no other type of K+ channel blockers, i.e. iberiotoxin, charybdotoxin or glibenclamide. These findings suggest that cannabinoid receptors inhibit Ca2+ influx into rat brain nerves via the activation of CB1 receptors and the opening of voltage-sensitive A-type K+ channels. Copyright (C) 2006 S. Karger AG, Basel.