Tolerance to cannabinoid response on the myenteric plexus of guinea-pig ileum and human small intestinal strips

Authors


Research Center Sanofi-Midy, Exploratory Research Department, Sanofi–aventis S.p.A., Via G.B. Piranesi 38, Milan 20137, Italy. E-mail: tiziano.croci@sanofi-aventis.com

Abstract

  • 1We 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 CB1 receptor antagonist rimonabant in control and tolerant strips.
  • 2(+) WIN 55,212-2 inhibited guinea-pig (IC50 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 (pA2, 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, IC50 39 and 43 nM.
  • 3Unlike 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 (EC50 100 nM) with a maximal effect of 123%.
  • 4In 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%).
  • 5This 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

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