The endocannabinoid system and the molecular basis of paralytic ileus in mice.
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.
Mascolo
Nicola
N
Department of Experimental Pharmacology, University of Naples Federico II, 80131 Naples, Italy.
Izzo
Angelo A
AA
Ligresti
Alessia
A
Costagliola
Anna
A
Pinto
Luisa
L
Cascio
Maria G
MG
Maffia
Pasquale
P
Cecio
Aldo
A
Capasso
Francesco
F
Di Marzo
Vincenzo
V
D000818:Animals; D001095:Arachidonic Acids / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D017615:Enteric Nervous System / Q000737:chemistry; D005769:Gastrointestinal Motility / Q000187:drug effects; D007418:Intestinal Pseudo-Obstruction / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007421:Intestine, Small / Q000737:chemistry / Q000294:innervation; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000737:chemistry; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000077285:Rimonabant; C078814:anandamide