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

1 We have studied the effect of cannabinoid agonists (CP 55,940 and cannabinol) on intestinal motility in a model of intestinal inflammation (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(-1)) and cannabinol (10-3000 nmol mouse(-1)) were more active in delaying intestinal motility in croton oil-treated mice than in control mice. These inhibitory effects were counteracted by the selective cannabinoid CB1 receptor antagonist SR141716A (16 nmol mouse(-1)). SR141716A (1-300 nmol mouse(-1)), administered alone, increased intestinal motility to the same extent in both control and croton oil-treated mice 3 Croton oil-induced intestinal inflammation was associated with an increased expression of CB1 receptor, an unprecedented example of up-regulation of cannabinoid receptors during inflammation. 4 High levels of anandamide and 2-arachidonylglycerol were detected in the small intestine, although no differences were observed between control and croton oil-treated mice; by contrast anandamide amidohydrolase activity increased 2 fold in the inflamed small intestine. 5 It is concluded that inflammation of the gut increases the potency of cannabinoid agonists possibly by 'up-regulating' CB1 receptor expression; in addition, endocannabinoids, whose turnover is increased in inflamed gut, might tonically inhibit intestinal motility.