Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti‐inflammatory agent

Abstract

Background and Purpose: Palmitoylethanolamide (PEA) acts via several targets, including cannabinoid CB1 and CB 2 receptors, transient receptor potential vanilloid type‐1 (TRPV1) ion channels, peroxisome proliferator‐activated receptor alpha (PPAR α) and orphan G protein‐coupled receptor 55 (GRR55), all involved in the control of intestinal inflammation. Here, we investigated the effect of PEA in a murine model of colitis. Experimental Approach: Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters and by histology; intestinal permeability by a fluorescent method; colonic cell proliferation by immunohistochemistry; PEA and endocannabinoid levels by liquid chromatography mass spectrometry; receptor and enzyme mRNA expression by quantitative RT‐PCR. Key Results: DNBS administration caused inflammatory damage, increased colonic levels of PEA and endocannabinoids, down‐regulation of mRNA for TRPV1 and GPR55 but no changes in mRNA for CB 1, CB 2 and PPARα. Exogenous PEA (i.p. and/or p.o., 1 mg·kg−1) attenuated inflammation and intestinal permeability, stimulated colonic cell proliferation, and increased colonic TRPV1 and CB 1 receptor expression. The anti‐inflammatory effect of PEA was attenuated or abolished by CB 2 receptor, GPR55 or PPARα antagonists and further increased by the TRPV1 antagonist capsazepine. Conclusions and Implications: PEA improves murine experimental colitis, the effect being mediated by CB 2 receptors, GPR55 and PPARα, and modulated by TRPV1 channels.