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Br J Pharmacol. 2015 Jun;172(12):3099-111. doi: 10.1111/bph.13114. Epub 2015 Apr 23.

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

Author information

1
Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
2
Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB, Canada.
3
Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
4
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Rome, Italy.
5
Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
6
II Medical Department, Klinikum Groshadern, Ludwig Maximilians University of Munich, Munich, Germany.

Abstract

BACKGROUND AND PURPOSE:

Endocannabinoids are a family of lipid mediators 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-α (DAGLα), which is involved in biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG).

EXPERIMENTAL APPROACH:

Cannabinoid CB1 receptor-deficient, wild-type control and C3H/HeJ mice, a genetically constipated strain, were used. The distribution of DAGLα in the enteric nervous system was examined by immunohistochemistry. 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 faecal output in vivo. Endocannabinoid 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 colocalized with the vesicular acetylcholine transporter in cholinergic nerves. In normal mice, inhibiting DAGL reversed both pharmacologically reduced intestinal contractility and pharmacologically prolonged whole gut transit. Moreover, inhibiting DAGL normalized faecal output in constipated C3H/HeJ mice. In colons incubated with scopolamine, 2-AG was elevated while inhibiting DAGL normalized 2-AG levels.

CONCLUSIONS AND IMPLICATIONS:

DAGLα was expressed in the enteric nervous system of mice and its inhibition reversed 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.

PMID:
25684407
PMCID:
PMC4459026
DOI:
10.1111/bph.13114
[Indexed for MEDLINE]
Free PMC Article

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