Abstract
We examined the effects of cannabinoid receptor agonists on <sup>45</sup>Ca<sup>2+</sup> 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-yl](1-naphthyl)methanone (WIN 55212-2) dose-dependently inhibited <sup>45</sup>Ca<sup>2+</sup> uptake in rat synaptosomes. Only an endogenous cannabinoid receptor agonist, anandamide, dose-dependently inhibited <sup>45</sup>Ca<sup>2+</sup> 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 <sup>45</sup>Ca<sup>2+</sup> 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 <sup>45</sup>Ca<sup>2+</sup> uptake in rat synaptosomes were reversed by the pretreatment of a voltage-sensitive A-type K<sup>+</sup> channel blocker, dendrotoxin, but no other type of K<sup>+</sup> channel blockers, i.e. iberiotoxin, charybdotoxin or glibenclamide. These findings suggest that cannabinoid receptors inhibit Ca<sup>2+</sup> influx into rat brain nerves via the activation of CB1 receptors and the opening of voltage-sensitive A-type K<sup>+</sup> channels.
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