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

Abstract

BACKGROUND AND PURPOSEEndocannabinoids 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 APPROACHCannabinoid 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 RESULTSDAGLα 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 IMPLICATIONSDAGLα 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. Abbreviations

Chinese Herbal Medicine (MaZiRenWan) Improves Bowel Movement in Functional Constipation Through Down-Regulating Oleamide

“…Animal studies demonstrated the regulation of oleamide by MZRW possibly through augmentation of FAAH-mediated degradation. Bashashati et al proposed that inhibiting endocannabinoid biosynthesis could be a novel approach for constipation treatment, which has been validated by animal studies (Bashashati et al, 2012;Bashashati et al, 2015). Very interestingly, our findings suggest a novel FC treatment approach: enhancing endocannabinoid degradation by promoting the expression/activity of intestinal FAAH.…”

The Role of the Endocannabinoid System in the Brain–Gut Axis

“…Proof of concept for this idea come from studies using DAGL and FAAH inhibitors. Inhibitors of DAGL have been examined in models of constipation; they effectively normalized slowed transit in opioid-induced constipation and in congenital slow-transit constipation 90 . Conversely, inhibiting the degradation of endocannabinoids, by blocking FAAH, has antidiarrheal and anti-nociceptive effects in models of accelerated motility and in mice with oil of mustard-induced colitis, respectively 91, 92 .…”

Gastrointestinal Adverse Events of Cannabinoid 1 Receptor Inverse Agonists suggest their Potential Use in Irritable Bowel Syndrome with Constipation: A Systematic Review and Meta-Analysis

“…Indeed, studies already have addressed the endocannabinoids in the treatment of constipation. Bashahati et al [36] found that by inhibiting diacylglycerol lipase-α, enzyme involved in biosynthesis of 2-AG, fecal output in genetically constipated mouse strain is normalized.…”