Abstract
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.
Highlights
Pain is considered to protect the organism of tissue damage and harm (Kuner and Flor, 2016; Peirs and Seal, 2016)
Injection of 9-hydroxyoctadecadienoic acid (HODE) during oxaliplatin-induced peripheral neuropathic pain (OIPN) causes increased mechanical hypersensitivity in vivo that seems to be mediated by a protein kinase C (PKC)-dependent mechanism, whereas direct injection into the paw of naïve wild-type mice had no effect on nociceptive behavior (Hohmann et al, 2017) (Table 1B)
While the various functions of prostanoid and cannabinoid receptors have previously been reviewed (Manzanares et al, 2006; Narumiya, 2007), we focus on recently described lipid G protein coupled receptors (GPCR) that may be involved in pathogenesis of persistent and neuropathic pain and may represent targets for the development of novel analgesics (Figure 3)
Summary
Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. 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. 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.
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