title: The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels.
abstract: OBJECTIVE
  Palmitoylethanolamide (PEA) is an endogenous congener of anandamide and potentiates its actions at cannabinoid CB1 and CB2 receptors, and at transient receptor potential vanilloid type-1 (TRPV1) channels. The other endocannabinoid, 2-arachidonoylglycerol (2-AG), was recently suggested to act as a TRPV1 channel agonist. We investigated if PEA enhanced levels of 2-AG in vitro or in vivo and 2-AG activity at TRPV1 channels.
  
  
  METHODS
  Endogenous lipid levels were measured by LC-MS in (i) human keratinocytes incubated with PEA (10-20 μM, 40 min, 6 and 24 h, 37°C); (ii) the blood of spontaneously Ascaris suum hypersensitive beagle dogs given a single oral dose of ultramicronized PEA (30 mg·kg(-1), 1, 2, 4 and 8 h from administration); (iii) the blood of healthy volunteers given a single oral dose of micronized PEA (300 mg, 2, 4 and 6 h from administration). Effects of 2-AG at TRPV1 channels were assessed by measuring intracellular Ca(2+) in HEK-293 cells over-expressing human TRPV1 channels.
  
  
  RESULTS
  PEA elevated 2-AG levels in keratinocytes (∼3-fold) and in human and canine plasma (∼2 and ∼20-fold respectively). 2-AG dose-dependently raised intracellular Ca(2+) in HEK-293-TRPV1 cells in a TRPV1-dependent manner and desensitized the cells to capsaicin. PEA only slightly enhanced 2-AG activation of TRPV1 channels, but significantly increased 2-AG-induced TRPV1 desensitization to capsaicin (IC50 from 0.75 ± 0.04 to 0.45 ± 0.02 μM, with PEA 2 μM).
  
  
  CONCLUSIONS
  These observations may explain why several effects of PEA are attenuated by cannabinoid receptor or TRPV1 channel antagonists.
  
  
  BACKGROUND
  This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.|Epitech Group, Saccolongo, Padua, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.|Epitech Group, Saccolongo, Padua, Italy.
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.affiliation: Departament de Farmacología, Facultat de Veterinària, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Cerrato
authors.affiliation: Epitech Group, Saccolongo, Padua, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Fusco
authors.affiliation: Departament de Farmacología, Facultat de Veterinària, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Puigdemont
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000293:Adolescent; D000328:Adult; D000577:Amides; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000097:blood*; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D063388:Endocannabinoids / Q000097:blood*; D004983:Ethanolamines / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005989:Glycerides / Q000097:blood*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010169:Palmitic Acids / Q000378:metabolism / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; D010169:Palmitic Acids; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C005958:palmidrol; C094503:glyceryl 2-arachidonate; D002211:Capsaicin; D002118:Calcium