The oxidized linoleic acid metabolite 12,13-DiHOME mediates thermal hyperalgesia during inflammatory pain

Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Jul;1863(7):669-678. doi: 10.1016/j.bbalip.2018.03.012. Epub 2018 Apr 4.


Eicosanoids play a crucial role in inflammatory pain. However, there is very little knowledge about the contribution of oxidized linoleic acid metabolites in inflammatory pain and peripheral sensitization. Here, we identify 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME), a cytochrome P450-derived linoleic acid metabolite, as crucial mediator of thermal hyperalgesia during inflammatory pain. We found 12,13-DiHOME in increased concentrations in peripheral nervous tissue during acute zymosan- and complete Freund's Adjuvant-induced inflammatory pain. 12,13-DiHOME causes calcium transients in sensory neurons and sensitizes the transient receptor potential vanilloid 1 (TRPV1)-mediated intracellular calcium increases via protein kinase C, subsequently leading to enhanced TRPV1-dependent CGRP-release from sensory neurons. Peripheral injection of 12,13-DiHOME in vivo causes TRPV1-dependent thermal pain hypersensitivity. Finally, application of the soluble epoxide hydrolase (sEH)-inhibitor TPPU reduces 12,13-DiHOME concentrations in nervous tissue and reduces zymosan- and CFA-induced thermal hyperalgesia in vivo. In conclusion, we identify a novel role for the lipid mediator 12,13-DiHOME in mediating thermal hyperalgesia during inflammatory pain and propose a novel mechanism that may explain the antihyperalgesic effects of sEH inhibitors in vivo.

Keywords: Inflammatory pain; Oxidized linoleic acid metabolites (OLAMs); TPPU; TRPV1; Thermal hyperalgesia; sEH-inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Behavior, Animal / drug effects
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Epoxide Hydrolases / antagonists & inhibitors
  • Epoxide Hydrolases / metabolism
  • Female
  • Freund's Adjuvant / toxicity
  • Hot Temperature / adverse effects
  • Humans
  • Hyperalgesia / drug therapy
  • Hyperalgesia / etiology
  • Hyperalgesia / pathology*
  • Inflammation / chemically induced
  • Inflammation / complications*
  • Linoleic Acid / metabolism
  • Male
  • Mice
  • Oleic Acids / metabolism*
  • Oxidation-Reduction / drug effects
  • Pain / drug therapy
  • Pain / etiology
  • Pain / pathology*
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Protein Kinase C / metabolism
  • Sensory Receptor Cells / metabolism
  • TRPV Cation Channels / metabolism
  • Zymosan / toxicity


  • 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea
  • 12,13-dihydroxyoctadecenoic acid
  • Analgesics
  • Enzyme Inhibitors
  • Oleic Acids
  • Phenylurea Compounds
  • Piperidines
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Freund's Adjuvant
  • Zymosan
  • Linoleic Acid
  • Protein Kinase C
  • Epoxide Hydrolases
  • Ephx2 protein, mouse