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Tolerance to cannabinoid response on the myenteric plexus of guinea‐pig ileum and human small intestinal strips
Author(s) -
Guagnini Fabio,
Cogliati Paola,
Mukenge Sylvain,
Ferla Gianfranco,
Croci Tiziano
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706813
Subject(s) - myenteric plexus , agonist , cannabinoid receptor , cannabinoid , medicine , endocrinology , guinea pig , ileum , cannabinoid receptor agonists , small intestine , biology , rimonabant , pharmacology , tetrodotoxin , chemistry , receptor , immunohistochemistry
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 n M ) and human small intestine (56 n M ) contractions with similar potency before or after 48‐h incubation in drug‐free conditions; this effect was competitively antagonized by rimonabant (p A 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 n M . 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 n M ) 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.British Journal of Pharmacology (2006) 148 , 1165–1173. doi: 10.1038/sj.bjp.0706813