title: Tolerance to cannabinoid response on the myenteric plexus of guinea-pig ileum and human small intestinal strips.
abstract: 1. We studied tolerance to cannabinoid agonist action by comparing the in vitro inhibition of electrically evoked contractions of longitudinal muscle from small intestine of human and guinea-pig (myenteric plexus preparations) after 48-h incubation with the synthetic agonist (+) WIN 55,212-2. We also investigated the intrinsic response to the selective cannabinoid CB(1) receptor antagonist rimonabant in control and tolerant strips. 2. (+) WIN 55,212-2 inhibited guinea-pig (IC(50) 4.8 nM) and human small intestine (56 nM) contractions with similar potency before or after 48-h incubation in drug-free conditions; this effect was competitively antagonized by rimonabant (pA(2), 8.4, 8.2). A 48-h preincubation with (+) WIN 55,212-2, but not with (-) WIN 55,212-3, completely abolished the acute agonist response in both tissue preparations. The opiate K-receptor agonist U69593 inhibited human small intestine contractions with a similar potency in control and strips tolerant to (+) WIN 55,212-2, IC(50) 39 and 43 nM. 3. Unlike human tissue, in guinea-pig small intestine, which has a high level of endocannabinoids, rimonabant alone increased the twitches induced by the electrical field stimulation (EC(50) 100 nM) with a maximal effect of 123%. 4. In strips tolerant to (+) WIN 55,212-2, rimonabant markedly increased (155%) the electrical twitches in human ileum and in guinea-pig myenteric plexus smooth muscle (133%). 5. This study shows tolerance can be induced to the cannabinoids' action in intestinal strips of human and guinea-pig by long in vitro incubation with the agonist (+) WIN 55,212-2.
authors.affiliation: Research Center Sanofi-Midy, Exploratory Research Department, Sanofi-aventis S.p.A., Via G.B. Piranesi 38, Milan 20137, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Guagnini
authors.forename: Paola
authors.initials: P
authors.lastname: Cogliati
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mukenge
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Ferla
authors.forename: Tiziano
authors.initials: T
authors.lastname: Croci
mesh_terms: D000818:Animals; D048588:Benzoxazines; D004361:Drug Tolerance; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007583:Jejunum / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009197:Myenteric Plexus / Q000187:drug effects* / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D000077285:Rimonabant
chemical_list: D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant