title: Cannabinoid receptor antagonism and inverse agonism in response to SR141716A on cAMP production in human and rat brain.
abstract: 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)-4-methyl-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 WIN55,212-2 and abolished by N-ethylmaleimide, consistent with the involvement of cannabinoid CB(1) receptors through the activation of G(i/o) proteins. These results suggest a ligand-independent activity for cannabinoid CB(1) receptor signaling cascade in mammalian brain.
authors.affiliation: Department of Physiology and Pharmacology, Medical School, University of Cantabria, Avenida Herrera Oria s/n, 39011, Santander, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Mato
authors.forename: Angel
authors.initials: A
authors.lastname: Pazos
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Valdizán
mesh_terms: D000818:Animals; D048588:Benzoxazines; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis*; D006801:Humans; D008024:Ligands; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D000077285:Rimonabant
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000242:Cyclic AMP; D000077285:Rimonabant