Soluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain
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REVIEW
Soluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain Karen M. Wagner 1 & Aldrin Gomes 2 & Cindy B. McReynolds 1 & Bruce D. Hammock 1
# The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract The role of lipids in pain signaling is well established and built on decades of knowledge about the pain and inflammation produced by prostaglandin and leukotriene metabolites of cyclooxygenase and lipoxygenase metabolism, respectively. The analgesic properties of other lipid metabolites are more recently coming to light. Lipid metabolites have been observed to act directly at ion channels and G protein–coupled receptors on nociceptive neurons as well as act indirectly at cellular membranes. Cytochrome P450 metabolism of specifically long-chain fatty acids forms epoxide metabolites, the epoxy-fatty acids (EpFA). The biological role of these metabolites has been found to mediate analgesia in several types of pain pathology. EpFA act through a variety of direct and indirect mechanisms to limit pain and inflammation including nuclear receptor agonism, limiting endoplasmic reticulum stress and blocking mitochondrial dysfunction. Small molecule inhibitors of the soluble epoxide hydrolase can stabilize the EpFA in vivo, and this approach has demonstrated relief in preclinical modeled pain pathology. Moreover, the ability to block neuroinflammation extends the potential benefit of targeting soluble epoxide hydrolase to maintain EpFA for neuroprotection in neurodegenerative disease. Key Words Soluble epoxide hydrolase (sEH) . epoxy-fatty acids (EpFA) . inflammatory pain . neuropathic pain . analgesia.
Introduction In the last several decades, the understanding of the role of lipids in pain sensation has increased substantially, including the potential to target them as strategies to relieve pain. This understanding of targeting lipids through regulatory enzymes lagged behind its practice. An example is the long history of using salicin from willow bark as an analgesic well before the elucidation of the mechanism of action of aspirin inhibiting cyclooxygenase enzymes to modulate prostaglandin production [1]. The more recent example of endocannabinoid signaling and elucidation of endogenous lipids that serve as ligands at cannabinoid receptors also has a long history of engagement prior this mechanistic insight (for a review, see Pertwee [2]).
* Bruce D. Hammock [email protected] 1
Department of Entomology and Nematology and University of California Davis Comprehensive Cancer Center, University of California Davis, One Shields Avenue, Davis, California 95616, USA
2
Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California, USA
With increased knowledge of both the biological systems in which lipids play a role, as well as far more sensitive and quantitative technologies for assaying these systems, knowledge regarding the biological activity of endogenous lipids has greatly advanced. Here we will describe the role of lipids in pain sensation wit
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