The endocannabinoid system and the molecular basis of paralytic ileus in mice

Abstract

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.

Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves

“…Interestingly, VIP receptor desensitization did not affect the I sc response to capsaicin. Similarly, experiments with the VIP receptor antagonists VIP [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] (16) (14) did not affect the response to capsaicin. Indeed, in our preparations, these antagonists failed even to block the secretory response to serosally applied VIP (data not shown).…”

“…Studies of the physiological role of cannabinoids in the gastrointestinal tract are becoming increasingly important because of the finding that endocannabinoids are present in the gut (32). Endocannabinoids have been shown to be physiological regulators of gastrointestinal motor functions (27,33), but their role in the modulation of intestinal secretion under normal conditions has not been extensively investigated. However, there are recent data to show that an endogenous cannabinoid tone is important in regulating the extent of the secretory response to cholera toxin (20).…”

Pharmacological characterization of cannabinoid receptor activity in the rat‐isolated ileum myenteric plexus‐longitudinal muscle preparation

“…Although the guinea pig ileum has long served as a useful bioassay for describing the inhibitory action of cannabinoids on intestinal transit observed in the mouse or rat in vivo, it is important that isolated ileal tissues from the latter species are used for studying cannabinoid effects. First, because a large number of models of disturbed intestinal motility of man have been created using the rat and mouse (Izzo et al, 1999;2001;Mascolo et al, 2002;Mathison et al, 2004), and second, to date, the guinea pig has not been employed for investigating cannabinoid effects on ileal transit in vivo.…”

“…In the rat ileum, the mRNAs of both cannabinoid receptors and their expression have been both identified and mapped in the myenteric plexus Valenti et al, 2005;Duncan et al, 2008). Furthermore, a number of endogenous cannabinoid ligands, exemplified by arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG), (Gomez et al, 2002;Mascolo et al, 2002;Izzo et al, 2003;Fegley et al, 2005;Valenti et al, 2005), along with the mechanisms for their enzymatic inactivation (Katayama et al, 1997), have been shown to be present in the rat ileum. Therefore, the purpose of this study was to investigate whether the rat ileum myenteric plexuslongitudinal muscle (MPLM) preparation served as a suitable and robust in vitro ileal cannabinoid receptor bioassay by assessing the interaction between representatives of the four main classes of cannabinoid receptor agonists, that is AEA, 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)-cy clohexyl]-phenol (CP 55,940), D 9 -tetrahydrocannabinol (D 9 -THC) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl methyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalen ylmethanone mesylate (WIN 55,, with the CB1 and CB2 receptor selective antagonist /inverse agonists rimonabant and SR 144 528 respectively.…”

Effects of simultaneous treatment with PMX-DHP and sivelestat on endotoxaemia in conscious guinea pigs

“…Neutrophils release elastases and superoxide-derived free radicals that directly damage tissues. Platelets release 2-arachidonoil glycerol (2-AG), an endogenous cannabinoid, that regulates intestinal and vascular tones 2,3) .…”