title: Cross-tolerance and convergent dependence between morphine and cannabimimetic agent WIN 55,212-2 in the guinea-pig ileum myenteric plexus.
abstract: The cross-tolerance and convergent dependence between morphine and the cannabimimetic agent R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-+ ++benzoxazin-yl]-(1-naphthalenyl) methanone mesylate (WIN 55,212-2) were assessed in vitro on guinea-pig ileum. To induce tolerance and dependence the myenteric plexus-longitudinal muscle was incubated at 37 degrees C for 5 h with a fixed concentration representing the IC50 for each compound. Myenteric plexus-longitudinal muscle exposed to WIN 55,212-2 (5 x 10(-8) M) was less sensitive to its inhibitory effect on electrically evoked contractions than naive myenteric plexus-longitudinal muscle. The exposure to cannabinoid induced a parallel rightward shift in the lower part of the concentration-response curve of WIN 55,212-2 and a marked reduction in the maximal inhibitory effect of the drug. Myenteric plexus-longitudinal muscle tolerant to WIN 55,212-2 was subsensitive to the inhibitory effect of morphine on the twitch response. The cross-tolerance between WIN 55,212-2 and morphine was bidirectional. In fact, after 5 h the morphine (10(-7) M)-incubated myenteric plexus-longitudinal muscle was less sensitive to the inhibitory effect of WIN 55,212-2. The tissue tolerant to morphine or WIN 55,212-2 was tested for the presence of physical dependence. Naloxone (10(-5) M) produced a typical withdrawal contracture in morphine-tolerant myenteric plexus-longitudinal muscle which could be reduced by a 15-min pretreatment with WIN 55,212-2 (5 X 10(-8) M). In contrast, SR141716 (10(-6) M) [N-(piperidino)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyr azole-carboxamide], a concentration which fully antagonized the inhibitory effect of WIN 55,212-2 (10(-7) M) in control preparations, did not produce significant contracture in WIN 55,212-2-tolerant myenteric plexus-longitudinal muscle. The mechanisms underlying the cross-tolerance and convergent dependence remain to be ascertained.
authors.affiliation: Department of Biotechnology and Bioscience, Faculty of Sciences, University of Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Basilico
authors.forename: D
authors.initials: D
authors.lastname: Parolaro
authors.forename: M
authors.initials: M
authors.lastname: Colleoni
authors.forename: B
authors.initials: B
authors.lastname: Costa
authors.forename: G
authors.initials: G
authors.lastname: Giagnoni
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D048588:Benzoxazines; D002186:Cannabinoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004361:Drug Tolerance; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D009020:Morphine