title: A re-evaluation of 9-HODE activity at TRPV1 channels in comparison with anandamide: enantioselectivity and effects at other TRP channels and in sensory neurons.
abstract: OBJECTIVE
  Two oxidation products of linoleic acid, 9- and 13-hydroxy-octadecadienoic acids (HODEs), have recently been suggested to act as endovanilloids, that is, endogenous agonists of transient receptor potential vanilloid-1 (TRPV1) channels, thereby contributing to inflammatory hyperalgesia in rats. However, HODE activity at rat TRPV1 in comparison with the best established endovanilloid, anandamide, and its enantioselectivity and selectivity towards other TRP channels that are also abundant in sensory neurons have never been investigated.
  
  
  METHODS
  We studied the effect of 9(R)-HODE, 9(S)-HODE, (+/-)13-HODE, 15(S)-hydroxyanandamide and anandamide on [Ca(2+) ](i)  in HEK-293 cells stably expressing the rat or human recombinant TRPV1, or rat recombinant TRPV2, TRPA1 or TRPM8, and also the effect of 9(S)-HODE in rat dorsal root ganglion (DRG) neurons by calcium imaging.
  
  
  RESULTS
  Anandamide and 15(S)-hydroxyanandamide were the most potent endovanilloids at human TRPV1, whereas 9(S)-HODE was approximately threefold less efficacious and 75- and 3-fold less potent, respectively, and did not perform much better at rat TRPV1. The 9(R)-HODE and (+/-)13-HODE were almost inactive at TRPV1. Unlike anandamide and 15(S)-hydroxyanandamide, all HODEs were very weak at desensitizing TRPV1 to the action of capsaicin, but activated rat TRPV2 [only (+/-)13-HODE] and rat TRPA1, and antagonized rat TRPM8, at concentrations higher than those required to activate TRPV1. Finally, 9(S)-HODE elevated [Ca(2+) ](i)  in DRG neurons almost exclusively in capsaicin-sensitive cells but only at concentrations between 25 and 100 μM.
  
  
  CONCLUSIONS
  The present data suggest that HODEs are less important endovanilloids than anandamide.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.
authors.affiliation: Endocannabinoid Research Group, Istituto di Cibernetica, CNR, Pozzuoli, Naples, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.forename: Roberta
authors.initials: R
authors.lastname: Imperatore
authors.forename: Luigia
authors.initials: L
authors.lastname: Cristino
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Starowicz
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D063388:Endocannabinoids / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D044243:Linoleic Acids, Conjugated / Q000737:chemistry / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: C549837:15-hydroxyanandamide; D001095:Arachidonic Acids; D063388:Endocannabinoids; D044243:Linoleic Acids, Conjugated; D053284:Polyunsaturated Alkamides; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C024347:9-hydroxy-10,12-octadecadienoic acid; D002118:Calcium; C078814:anandamide