title: Palmitoylethanolamide normalizes intestinal motility in a model of post-inflammatory accelerated transit: involvement of CB₁ receptors and TRPV1 channels.
abstract: OBJECTIVE
  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, 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).
  
  
  METHODS
  Intestinal 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.
  
  
  RESULTS
  OM 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
  Intestinal 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.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Capasso
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Orlando
authors.forename: Ester
authors.initials: E
authors.lastname: Pagano
authors.forename: Teresa
authors.initials: T
authors.lastname: Aveta
authors.forename: Lorena
authors.initials: L
authors.lastname: Buono
authors.forename: Francesca
authors.initials: F
authors.lastname: Borrelli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Izzo
mesh_terms: D000577:Amides; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D007274:Injections, Intraperitoneal; D043183:Irritable Bowel Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009149:Mustard Plant; D010169:Palmitic Acids / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D010938:Plant Oils / Q000008:administration & dosage; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D004983:Ethanolamines; D010169:Palmitic Acids; D010880:Piperidines; D010938:Plant Oils; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C005958:palmidrol; D000077285:Rimonabant; C027793:mustard oil