title: Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents.
abstract: The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9- and 13-HODE and their metabolites, 9- and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs.
authors.affiliation: Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78227, USA.
authors.forename: Amol M
authors.initials: AM
authors.lastname: Patwardhan
authors.forename: Armen N
authors.initials: AN
authors.lastname: Akopian
authors.forename: Nikita B
authors.initials: NB
authors.lastname: Ruparel
authors.forename: Anibal
authors.initials: A
authors.lastname: Diogenes
authors.forename: Susan T
authors.initials: ST
authors.lastname: Weintraub
authors.forename: Charis
authors.initials: C
authors.lastname: Uhlson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Hargreaves
mesh_terms: D000818:Animals; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006358:Hot Temperature; D008024:Ligands; D019787:Linoleic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D010146:Pain; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated; D008024:Ligands; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; C495366:hydroxyoctadecadienoic acid; D019787:Linoleic Acid; D010100:Oxygen