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

• Published in: Biochimica et biophysica acta. Molecular and cell biology of lipids 2018-07, Vol.1863 (7), p.669-678
• Main Authors: Zimmer, Béla, Angioni, Carlo, Osthues, Tabea, Toewe, Andy, Thomas, Dominique, Pierre, Sandra C., Geisslinger, Gerd, Scholich, Klaus, Sisignano, Marco
• Format: Article
• Language: English
• Subjects: 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; Inflammatory pain; Linoleic Acid - metabolism; Male; Mice; Oleic Acids - metabolism; Oxidation-Reduction - drug effects; Oxidized linoleic acid metabolites (OLAMs); Pain - drug therapy; Pain - etiology; Pain - pathology; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Piperidines - pharmacology; Piperidines - therapeutic use; Protein Kinase C - metabolism; sEH-inhibitor; Sensory Receptor Cells - metabolism; Thermal hyperalgesia; TPPU; TRPV Cation Channels - metabolism; TRPV1; Zymosan - toxicity
• ISSN: 1388-1981; 1879-2618
• DOI: 10.1016/j.bbalip.2018.03.012

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. •The concentrations of the oxidized lipid 12,13-DiHOME increase during inflammatory pain.•12,13-DiHOME induces thermal pain hypersensitivity via TRPV1.•The sEH-inhibitor TPPU reduces DiHOME concentrations in nervous tissue in vivo.•TPPU reduces both CFA- and zymosan-induced thermal hyperalgesia in vivo.•A novel mechanism of how sEH-inhibition reduces thermal hyperalgesia is proposed.