Soluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain

Soluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain Karen M. Wagner, Aldrin Gomes, Cindy B. McReynolds & Bruce D. Hammock Neurotherapeutics The Journal of the American Society for Experimental Neurotherapeutics ISSN 1933-7213 Neurotherapeutics DOI 10.1007/s13311-020-00916-4 1 23 Your article is protected by copyright and all rights are held exclusively by The American Society for Experimental NeuroTherapeutics, Inc.. This e-offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. 1 23 Author's personal copy Neurotherapeutics https://doi.org/10.1007/s13311-020-00916-4 REVIEW Soluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain Karen M. Wagner1 & Aldrin Gomes2 & Cindy B. McReynolds1 & Bruce D. Hammock1 # 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 endo- plasmic 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 neuro- protection in neurodegenerative disease. Key Words Soluble epoxide hydrolase (sEH) . epoxy-fatty acids (EpFA) . inflammatory pain . neuropathic pain . analgesia. Introduction With increased knowledge of both the biological systems in which lipids play a role, as well as far more sensitive and In the last several decades, the understanding of the role of quantitative technologies for assaying these systems, knowl- lipids in pain sensation has increased substantially, including edge regarding the biological activity of endogenous lipids the potential to target them as strategies to relieve pain. This has greatly advanced. Here we will describe the role of lipids understanding of targeting lipids through regulatory enzymes in pain sensation with special attention to epoxy-fatty acid lagged behind its practice. An example is the long history of (EpFA) bioactive metabolites that have been more recently using salicin from willow bark as an analgesic well before the described given new tools to investigate their biology. elucidation of the mechanism of action of aspirin inhibiting cyclooxygenase enzymes to modulate prostaglandin produc- tion [1]. The more recent example of endocannabinoid signaling and elucidation of endogenous lipids that serve as ligands Pain Sensation and Lipids at cannabinoid receptors also has a long history of engagement prior this mechanistic insight (for a review, see Pertwee [2]). Nociception, the sensing of pain, is mediated by the action of a specialized subset of sensory afferent neurons called nociceptors. Nociceptors are activated in response to thermal, mechanical, and chemical stimuli through a variety of mech- * Bruce D. Hammock anisms. Although not an exhaustive list, ion channel modula- [email protected] tion including transient receptor potential (TRP) channels, G protein–coupled receptor (GPCR) activation, and alteration of 1 Department of Entomology and Nematology and University of California Davis Comprehensive Cancer Center, University of cellular membranes are all described mechanisms in which California Davis, One Shields Avenue, Davis, California 95616, lipids act to impact signaling in nociception [3]. USA Pain has been described alongside inflammation since the 2 Department of Neurobiology, Physiology, and Behavior, University Roman Aulus Celsus in the first century AD, and it is now of California, Davis, California, USA well known from the work of Sune Bergstrom, Bengt Author's personal copy Wagner et al. Samuelsson, John Vane, and others to result in part from lipid proven valuable because there is now the knowledge that not metabolites of cyclooxygenase isozymes, the prostaglandins only PUFA of several different classes are substrates for sev- acting at GPCRs (in this case, the EP receptors named for eral metabolic enzymes, but also that the product lipid metab- prostaglandin E agonism) [4]. Raphael Mechoulam and col- olites of these can be further substrates of these same enzymes. laborators were able to identify another type of bioactive lipid Arachidonic acid (ARA), a 20-carbon length PUFA, is arachidonoylethanolamide (AEA) named anandamide that ag- converted by CYP450 enzymes into epoxide metabolites at onized the GPCR cannabinoid receptors [5]. Sensitization of any or several of the 4 double bonds in the molecule. The neurons to painful stimuli can also occur via lipid agonism of metabolites formed from ARA maintain their 20-carbon TRP channels in thermal sensitivity. David Julius demonstrat- length structure and are generalized with all eicosanoids ed the activity of TRP channels in the 1990s, first with exog- (eicosa Greek for 20). However, the omega-3 long-chain fatty enous ligands like capsaicin; however, they are now known to acids, DHA in particular, are also substrates of the major me- be agonized by endogenous lipids as well [6, 7]. Although this tabolizing enzymes of what is classically known as the ARA review will focus on monoepoxide lipid signaling mediators cascade and have demonstrated competition with ARA in en- formed from fatty acids, there is evidence of lipids such as zyme assays in vitro [17, 18]. The ARA cascade generates phosphatidylinositol 4,5-bisphosphate (PIP2) acting directly oxidation metabolites by the cyclooxygenase and on ion channels [8]. Interestingly, there is also a growing body lipoxygenase enzyme families. These metabolites have been of literature on the effects of lysophosphatidic acid (LPA) well described for ARA including their synthesis and bioac- which signals via a GPCR with 6 subtypes and is indicated tivity and are mostly, but not exclusively, pro-inflammatory. in the generation of pain [9, 10]. In addition to these actions, Some of these metabolites such as prostaglandin E2 have a there is also accumulating evidence about lipid–protein inter- more complex role in inflammation being initially pro- actions that modulate signaling by indirect mechanisms affect- inflammatory and later regulating resolution in at least some ing the properties of cellular membranes [11, 12]. models [19]. The monoepoxygenated EpFA generated by cy- The lipid ligands including the EpFA are unlike peptide tochrome P450 enzymes, on the other hand, are anti- neurotransmitters. They are released or synthesized on de- inflammatory and balance the action of other pro- mand and are not stored in vesicles for release into synaptic inflammatory eicosanoids (Fig. 1). terminals. They have putative GPCR mechanisms although Thus, the ARA-derived metabolites are known as eicosa- they may act indirectly to influence ion channel proteins or noids and epoxyeicosatrienoic acids (EETs) are classical ei- the membranes in which they reside. Typically, as is the case cosanoids as EpFA. However, other long-chain PUFA such as with EpFA, they are tightly regulated by the activity of regu- docosahexaenoic acid (DHA) and eicosapentaenoic acid lating enzymes that degrade them or reincorporate them into (EPA) are also substrates of the CYP450 enzymes and form membranes [13, 14]. Some lipids such as AEA and a few several regioisomers of epoxide metabolites based on the EpFA that conform to the structural requirements of TRP lipid number of double bonds available for epoxidation [20]. The agonism also have been demonstrated to additionally activate metabolites are the epoxydocosapentanoic acids (EDPs) and TRP channels [10, 15]. Given the pleiotropic functions of the epoxyeicosatetraenoic acids (EEQ, so named quaternary these lipid classes, the question remains what role the TRP to avoid confusion with trienoic acids) of DHA and EPA, currents they produce serve in comparison to their more potent respectively. All of these classes of long-chain PUFA-derived and contrasting analgesic actions in vivo. EpFA have shown anti-nociceptive action and all of the EpFA The confounds of researching the role of analgesic lipids have been shown to be metabolized to diols rapidly by the in

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