Cannabinoid CB₁‐receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation

Abstract

1 We have studied the eect of cannabinoid agonists (CP 55,940 and cannabinol) on intestinal motility in a model of intestinal in¯ammation (induced by oral croton oil in mice) and measured cannabinoid receptor expression, endocannabinoids (anandamide and 2-arachidonylglycerol) and anandamide amidohydrolase activity both in physiological and pathophysiological states. 2 CP 55,940 (0.03 ± 10 nmol mouse 71) and cannabinol (10 ± 3000 nmol mouse 71 ) were more active in delaying intestinal motility in croton oil-treated mice than in control mice. These inhibitory eects were counteracted by the selective cannabinoid CB 1 receptor antagonist SR141716A (16 nmol mouse 71). SR141716A (1 ± 300 nmol mouse 71 ), administered alone, increased intestinal motility to the same extent in both control and croton oil-treated mice 3 Croton oil-induced intestinal in¯ammation was associated with an increased expression of CB 1 receptor, an unprecedented example of up-regulation of cannabinoid receptors during in¯ammation. 4 High levels of anandamide and 2-arachidonylglycerol were detected in the small intestine, although no dierences were observed between control and croton oil-treated mice; by contrast anandamide amidohydrolase activity increased 2 fold in the in¯amed small intestine. 5 It is concluded that in¯ammation of the gut increases the potency of cannabinoid agonists possibly by`up-regulating' CB 1 receptor expression; in addition, endocannabinoids, whose turnover is increased in in¯amed gut, might tonically inhibit intestinal motility.

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…In another study of LPS-induced inflammation, the FAAH inhibitor AM3506 normalized hypermotility in a CB 1 -and CB 2 -dependent manner, whereas colonic propulsion was CB 1 -dependent [21]. Interestingly, the effect of cannabinoids in cases of inflammatory hypermotility occurred at lower doses than in control states [8,22]. This could be due to the increased receptor expression during inflammation, to increased coupling of the receptor to effectors proteins, or both.…”

“…Under normal conditions, CB 1 mediates the effects of cannabinoids on motility; however, in inflammatory states both CB 1 and CB 2 receptor activation may reduce inflammation-induced hypermotility. For instance, in lipopolysaccharide (LPS)-induced intestinal inflammation, hypermotility was normalized following CB 2 (but not CB 1 ) activation [19,20], whereas in croton oil-induced hypermotility CB 2 antagonism did not reverse the effect of the cannabinoid agonist CP55,940 [8]. In another study of LPS-induced inflammation, the FAAH inhibitor AM3506 normalized hypermotility in a CB 1 -and CB 2 -dependent manner, whereas colonic propulsion was CB 1 -dependent [21].…”

“…Cannabinoids and endocannabinoid degradation inhibitors decrease intestinal motility, peristalsis, and colonic propulsion in rodents, primarily in a CB 1 -dependent manner [7][8][9][10][11][12]. Accordingly, [8,9,13,14]. It is likely that cannabinoids inhibit contractility by reducing acetylcholine release from enteric nerves because they do not inhibit contractions produced by exogenous administration of acetylcholine but reduce electrically-evoked acetylcholine release from myenteric nerves [7,15,16].…”

“…Cannabinoids and endocannabinoid degradation inhibitors decrease intestinal motility, peristalsis, and colonic propulsion in rodents, primarily in a CB 1 -dependent manner [7][8][9][10][11][12]. Accordingly, [8,9,13,14].…”

Cannabinoids and their medicinal potential

“…77 Pharmacological studies have demonstrated that anandamide and various CB 1 agonists inhibit gastrointestinal motility in rodens in vivo and in isolated ileum and colon from both animals and humans. 20,80,81 In clinical trials with rimonabant for nicotine cessation or obesity, it was seen that incidence of diarrhea was higher in patients receiving rimonabant than with placebo. Therefore this suggests that blocking CB 1 receptors accelerated gastrointestinal transit and secretions 20 , so CB 1 agonists may prove useful in diarrhea-predominant IBS while CB 1 antagonists can help in constipation-predominant IBS.…”