Palmitoylethanolamide normalizes intestinal motility in a murine model of post-inflammatory accelerated transit: involvement of CB1 receptors and TRPV1.

Abstract BACKGROUND AND PURPOSE: Palmitoylethanolamide (PEA), a naturally-occurring acylethanolamide chemically related to the endocannabinoid anandamide, interacts with targets that have been identified in peripheral nerves controlling gastrointestinal motility, i.e. cannabinoid (CB1 and CB2 ) receptors, transient receptor potential vanilloid type-1 (TRPV1), and peroxisomal proliferator activated receptor ? (PPAR?). 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(IBS)-like] EXPERIMENTAL APPROACH: Intestinal inflammation was induced by intracolonic administration of oil of mustard (OM). Mice were tested for motility and biochemical/molecular biology changes four weeks later. Palmitoylethanolamide, oleoylethanolamide and endocannabinoid levels were measured by chromatography-mass spectrometry, and receptor and enzyme mRNA expression by quantitative reverse transcription-PCR. KEY RESULTS: OM induced transient colitis and a functional post-inflammatory increase in upper gastrointestinal transit which was associated to elevation of intestinal anandamide (but not 2-arachidonoylglycerol, palmitoylethanolamide or oleoylethanolamide) levels and down-regulation of TRPV1 mRNA expression. Exogenous ultramicronized palmitoylethanolamide counteracted OM-induced increase in transit and tended to increase anandamide levels. Palmitic acid had a weaker effect on transit. The inhibitory effect of palmitoylethanolamide on transit was counteracted by rimonabant (CB1 receptor antagonist), further increased by 5'-iodoresiniferatoxin (I-RTX, TRPV1 antagonist) and not significantly modified by the PPAR? antagonist GW6471. CONCLUSIONS AND IMPLICATIONS: Intestinal endocannabinoid and TRPV1 dysregulation were detected in a functional model of accelerated transit modeling some aspects of post-inflammatory IBS. Palmitoylethanolamide counteracted the accelerated transit, the effect being mediated by CB1 receptors (possibly via increased anandamide levels) and modulated by TRPV1 channels. This article is protected by copyright. All rights reserved.