Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation.

BACKGROUND AND PURPOSE:

Endocannabinoids are a family of lipid mediators that are involved in the regulation of gastrointestinal (GI) motility. The expression, localization and function of their biosynthetic enzymes in the GI tract are not well understood. Here we examined the expression, localization and function of the enzyme diacylglycerol lipase (DAGLα), involved in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG).

EXPERIMENTAL APPROACH:

Cannabinoid (CB)1-deficient, wildtype control and C3H/HeJ mice, a genetically constipated model, were used. The distribution of DAGLα in the enteric nervous system was examined by immunohistochemistry. The effects of the DAGL inhibitors, Orlistat and OMDM-188 on pharmacologically induced GI hypomotility were assessed by measuring intestinal contractility in vitro and whole gut transit or fecal output in vivo. EC levels were measured by mass spectrometry.

KEY RESULTS:

DAGLα was expressed throughout the GI tract. In the intestine, unlike DAGLβ, DAGLα immunoreactivity was prominently expressed in the enteric nervous system; in the myenteric plexus, it was co-localized with the vesicular acetylcholine transporter in cholinergic nerves. In normal mice, inhibiting DAGL significantly reversed both pharmacologically reduced intestinal contractility and pharmacologically prolonged whole gut transit. Moreover, inhibiting DAGL normalized fecal output in constipated C3H/HeJ mice. In the colon incubated with scopolamine, 2-AG was elevated while inhibiting DAGL normalized 2-AG levels.

CONCLUSIONS AND IMPLICATIONS:

DAGLα is expressed in the enteric nervous system and its inhibition reverses slowed GI motility, intestinal contractility and constipation through 2-AG and CB1 receptor mediated mechanisms. Our data suggest that DAGLα inhibitors may be promising candidates for the treatment of constipation.
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