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.