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.

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, i.p.) but not by SR144528 (52 nmol mouse 71 , i.p.) both in control and croton-oil treated mice. 5 Ganglionic blockade with hexamethonium (69 nmol mouse 71 , i.p.) did not modify the inhibitory eect of i.p.-injected cannabinoid agonists either in control or in croton-oil treated mice. 6 The lower ED 50 values of cannabinoid drugs after i.c.v. administration suggest a central (CB 1 ) site of action. However, a peripheral site of action is suggested by the lack of eect of hexamethonium. In addition, croton oil-induced diarrhoea enhances the eect of cannabinoid agonists by a peripheral mechanism.

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The endocannabinoid system (i.e., the cannabinoid receptors and their endogenous ligands) plays an important role in the physiological control of intestinal motility. However, its participation in intestinal pathological states is still poorly understood. In the present study, we investigated the possible role of the endocannabinoid system in the pathogenesis of paralytic ileus, a pathological state consisting of decreased intestinal motility following peritonitis, surgery, or other noxious situations. Ileus was induced by i.p. administration of acetic acid, and gastrointestinal propulsion was assessed by the charcoal method. Endocannabinoid levels were measured by isotope-dilution gas chromatography-mass spectrometry, whereas cannabinoid CB1 receptors were identified by immunohistochemistry. Acetic acid administration inhibited gastrointestinal transit (ileus), and this effect was accompanied by increased levels of the endocannabinoid anandamide compared with control mice and by overexpression of CB1 receptors in myenteric nerves. Furthermore, acetic acid-induced ileus was alleviated by the CB1 receptor antagonist SR141716A and worsened by VDM11, a selective inhibitor of anandamide cellular uptake (and hence inactivation). From these findings, it can be concluded that the intestinal hypomotility typical of paralytic ileus is due, at least in part, to the enhancement of anandamide levels and CB1 expression during this condition, and that selective, nonpsychotropic CB1 receptor antagonists could represent new drugs to treat this disorder.