Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB₁ receptors and TRPV1 channels

Abstract

BACKGROUND AND PURPOSEPalmitoylethanolamide (PEA), a naturally occurring acylethanolamide chemically related to the endocannabinoid anandamide, interacts with targets that have been identified in peripheral nerves controlling gastrointestinal motility, such as cannabinoid CB1 and CB2 receptors, TRPV1 channels and PPARα. Here, we investigated the effect of PEA in a mouse model of functional accelerated transit which persists after the resolution of colonic inflammation (post-inflammatory irritable bowel syndrome). EXPERIMENTAL APPROACHIntestinal inflammation was induced by intracolonic administration of oil of mustard (OM). Mice were tested for motility and biochemical and molecular biology changes 4 weeks later. PEA, oleoylethanolamide and endocannabinoid levels were measured by liquid chromatography-mass spectrometry and receptor and enzyme mRNA expression by qRT-PCR. KEY RESULTSOM induced transient colitis and a functional post-inflammatory increase in upper gastrointestinal transit, associated with increased intestinal anandamide (but not 2-arachidonoylglycerol, PEA or oleoylethanolamide) levels and down-regulation of mRNA for TRPV1 channels. Exogenous PEA inhibited the OM-induced increase in transit and tended to increase anandamide levels. Palmitic acid had a weaker effect on transit. Inhibition of transit by PEA was blocked by rimonabant (CB1 receptor antagonist), further increased by 5′-iodoresiniferatoxin (TRPV1 antagonist) and not significantly modified by the PPARα antagonist GW6471. CONCLUSIONS AND IMPLICATIONSIntestinal endocannabinoids and TRPV1 channel were dysregulated in a functional model of accelerated transit exhibiting aspects of post-inflammatory irritable bowel syndrome. PEA counteracted the accelerated transit, the effect being mediated by CB1 receptors (possibly via increased anandamide levels) and modulated by TRPV1 channels.

Drug discovery approaches to irritable bowel syndrome

“…Three and 4 weeks after intracolonic oil of mustard, mice had significantly accelerated upper GI transit rates compared to control mice [102]. This post-inflammatory IBS-like model has been used to characterize endocannabinoid involvement in accelerated GI transit [103] which appears to be dysregulated with increased intestinal anandamide levels [104]. In this model of IBS-like enhanced transit, mudelta (eluxadoline, see addendum) reversed the increased upper intestinal transit in mice compared to control [105].…”

The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease

“…There is also increasing evidence that GPR55 is involved in the regulation of gut motility since its agonist O‐1602 was able to slow down whole gut transit in mice . Both PEA and OEA inhibit intestinal transit in mice but the mode of action is unclear because neither CB receptors nor PPARα seem to be involved in that process; however, in a mouse model of postinflammatory irritable bowel syndrome (IBS; mustard oil‐induced), inhibition of transit by PEA could be blocked with a CB 1 receptor antagonist, but was not significantly modified with a PPARα antagonist …”

Complementary and Alternative Medicine Strategies for Therapeutic Gut Microbiota Modulation in Inflammatory Bowel Disease and their Next-Generation Approaches

“…These lipids can act as natural ligands for PPARα (OEA and PEA) [186, 187] TRPV1 (AEA and OEA) [169, 188, 189]. Other bioactive lipids belonging to the acylglycerol family, palmitoyl-glycerol (2-PG) and oleoylglycerol (2-OG), are also considered protective of barrier function [190–193].…”