Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 443, Issue 1-3, Pages 43-46Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S0014-2999(02)01575-3
Keywords
SR141716A; inverse agonism; cannabinoid system; adenylate cyclase
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The effects of cannabinoid drugs on CAMP production were examined in mammalian brain. The cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3,-d,e-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone (WIN55, 212-2) decreased forskolin-induced CAMP accumulation in a concentration-dependent manner (10(-8)-10(-5) M) in membranes from several rat and human brain regions, this effect being antagonized by 10(-5) M N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4methyl-1H-pyrazole-3-carboxamide (SR141716A). Furthermore, high micromolar concentrations of SR141716A evoked a dose-dependent increase in basal CAMP in rat cerebellum and cortex, as well as in human frontal cortex. This effect was antagonized by WTN55,212-2 and abolished by N-ethylmaleimide, consistent with the involvement of cannabinoid CB1 receptors through the activation of G(10) proteins. These results suggest a ligand-independent activity for cannabinoid CB1 receptor signaling cascade in mammalian brain. (C) 2002 Elsevier Science B.V. All rights reserved.
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