Cannabinoid receptor agonists inhibit Ca(2+) influx to synaptosomes from rat brain.
We examined the effects of cannabinoid receptor agonists on (45)Ca(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-yl](1-naphthyl)methanone (WIN 55212-2) dose-dependently inhibited (45)Ca(2+) uptake in rat synaptosomes. Only an endogenous cannabinoid receptor agonist, anandamide, dose-dependently inhibited (45)Ca(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 (45)Ca(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 (45)Ca(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 Ca(2+) influx into rat brain nerves via the activation of CB1 receptors and the opening of voltage-sensitive A-type K(+) channels.
Yoshihara
Shigemi
S
Department of Pediatrics, Dokkyo University School of Medicine, Mibu-machi, Japan. shigemi@dokkyomed.ac.jp
Morimoto
Hiroshi
H
Ohori
Makoto
M
Yamada
Yumi
Y
Abe
Toshio
T
Arisaka
Osamu
O
D000577:Amides; D000818:Animals; D048588:Benzoxazines; D001692:Biological Transport; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism*; D001892:Camphanes / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000494:pharmacology; D063388:Endocannabinoids; D004983:Ethanolamines; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010169:Palmitic Acids / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D000577:Amides; D048588:Benzoxazines; D001892:Camphanes; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D004546:Elapid Venoms; D063388:Endocannabinoids; D004983:Ethanolamines; D009025:Morpholines; D009281:Naphthalenes; D010169:Palmitic Acids; D010880:Piperidines; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C005958:palmidrol; C020273:dendrotoxin; D000077285:Rimonabant; D002118:Calcium