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Front. Pharmacol. | doi: 10.3389/fphar.2019.01147

Oxidized lipids in persistent pain states

  • 1Institute of Clinical Pharmacology, University Hospital Frankfurt, Germany
  • 2Fraunhofer IME - Translational Medicine and Pharmacology (TMP), Germany

Chemotherapy, nerve injuries or diseases like multiple sclerosis can cause pathophysiological processes of persistent and neuropathic pain. Thereby, the activation threshold of ion channels is reduced in peripheral sensory neurons to normally noxious stimuli like heat, cold, acid or mechanical due to sensitization processes. This leads to enhanced neuronal activity, which can result in mechanical allodynia, cold allodynia, thermal hyperalgesia, spontaneous pain and may initiate persistent and neuropathic pain. The treatment options for persistent and neuropathic pain patients are limited; for about 50 % of them, current medication is not efficient due to severe side effects or low response to the treatment. Therefore, it is of special interest to find additional treatment strategies. One approach is the control of neuronal sensitization processes. Herein, signaling lipids are crucial mediators and play an important role during the onset and maintenance of pain. As preclinical studies demonstrate, lipids may act as endogenous ligands or may sensitize transient receptor potential (TRP)-channels. Likewise, they can cause enhanced activity of sensory neurons by mechanisms involving G-protein coupled receptors and activation of intracellular protein kinases. In this regard, oxidized metabolites of the essential fatty acid linoleic acid, 9- and 13- hydroxyoctadecadienoic acid (HODE), their dihydroxy-metabolites (DiHOMEs), as well as epoxides of linoleic acid (EpOMEs) and of arachidonic acid (EETs), as well as lysophospholipids, sphingolipids and specialized pro-resolving mediators (SPMs) have been reported to play distinct roles in pain transmission or inhibition. Here, we discuss the underlying molecular mechanisms of the oxidized linoleic acid metabolites and eicosanoids. Furthermore, we critically evaluate their role as potential targets for the development of novel analgesics and for the treatment of persistent or neuropathic pain.

Keywords: Pain, TRP channels, linoleic acid metabolites, Eicosanoids, HODE, Inflammation, Inflammatory pain, Lipids, neuropathic pain

Received: 22 May 2019; Accepted: 05 Sep 2019.

Copyright: © 2019 Sisignano and Osthues. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Marco Sisignano, Institute of Clinical Pharmacology, University Hospital Frankfurt, Frankfurt, Germany,