K Wagner1, K S S Lee1, J Yang1, B D Hammock1. 1. Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California Davis, USA.
Abstract
BACKGROUND: Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega-3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs. Second, based on evidence that DHA and CYP450 metabolites elicit analgesia through opioid signalling, we investigated this as a possible mechanism of action. Third, we tested whether the analgesia mediated by epoxy fatty acids had similar rewarding effects as opioid analgesics. METHODS: We tested diabetic neuropathic wild-type and sEH null mice in a conditioned place preference assay for their response to EDPs, sEHI and antagonism of these treatments with naloxone, a mu-opioid receptor antagonist. RESULTS: The EDPs and sEH inhibitors were efficacious against chronic pain, and naloxone antagonized the action of both EDPs and sEH inhibitors. Despite this antagonism, the sEH inhibitors lacked reward side effects differing from opioids. CONCLUSIONS: The EpFA are analgesic against chronic pain differing from opioids which have limited efficacy in chronic conditions. SIGNIFICANCE: EDPs and sEHI mediate analgesia in modelled chronic pain and this analgesia is blocked by naloxone. However, unlike opioids, sEHI are highly effective in neuropathic pain models and importantly lack rewarding side effects.
BACKGROUND:Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega-3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs. Second, based on evidence that DHA and CYP450 metabolites elicit analgesia through opioid signalling, we investigated this as a possible mechanism of action. Third, we tested whether the analgesia mediated by epoxy fatty acids had similar rewarding effects as opioid analgesics. METHODS: We tested diabetic neuropathic wild-type and sEH null mice in a conditioned place preference assay for their response to EDPs, sEHI and antagonism of these treatments with naloxone, a mu-opioid receptor antagonist. RESULTS: The EDPs and sEH inhibitors were efficacious against chronic pain, and naloxone antagonized the action of both EDPs and sEH inhibitors. Despite this antagonism, the sEH inhibitors lacked reward side effects differing from opioids. CONCLUSIONS: The EpFA are analgesic against chronic pain differing from opioids which have limited efficacy in chronic conditions. SIGNIFICANCE: EDPs and sEHI mediate analgesia in modelled chronic pain and this analgesia is blocked by naloxone. However, unlike opioids, sEHI are highly effective in neuropathic pain models and importantly lack rewarding side effects.
Authors: Todd R Harris; Ahmed Bettaieb; Sean Kodani; Hua Dong; Richard Myers; Nipavan Chiamvimonvat; Fawaz G Haj; Bruce D Hammock Journal: Toxicol Appl Pharmacol Date: 2015-03-28 Impact factor: 4.219
Authors: Jennie L Conroy; Cheng Fang; Jun Gu; Scott O Zeitlin; Weizhu Yang; Jun Yang; Melissa A VanAlstine; Julia W Nalwalk; Phillip J Albrecht; Joseph E Mazurkiewicz; Abigail Snyder-Keller; Zhixing Shan; Shao-Zhong Zhang; Mark P Wentland; Melissa Behr; Brian I Knapp; Jean M Bidlack; Obbe P Zuiderveld; Rob Leurs; Xinxin Ding; Lindsay B Hough Journal: Nat Neurosci Date: 2010-02-07 Impact factor: 24.884
Authors: A G P Guedes; F Aristizabal; A Sole; A Adedeji; R Brosnan; H Knych; J Yang; S-H Hwang; C Morisseau; B D Hammock Journal: J Vet Pharmacol Ther Date: 2017-10-25 Impact factor: 1.786
Authors: Karen Wagner; Jennifer Gilda; Jun Yang; Debin Wan; Christophe Morisseau; Aldrin V Gomes; Bruce D Hammock Journal: Behav Brain Res Date: 2017-03-01 Impact factor: 3.332
Authors: Sung Hee Hwang; Karen Wagner; Jian Xu; Jun Yang; Xichun Li; Zhengyu Cao; Christophe Morisseau; Kin Sing Stephen Lee; Bruce D Hammock Journal: Bioorg Med Chem Lett Date: 2016-12-02 Impact factor: 2.823
Authors: Naoki Matsumoto; Nalin Singh; Kin Sing Lee; Bogdan Barnych; Christophe Morisseau; Bruce D Hammock Journal: Prostaglandins Other Lipid Mediat Date: 2022-06-30 Impact factor: 3.813
Authors: Maris A Cinelli; Jun Yang; Amy Scharmen; Joey Woodman; Lalitha M Karchalla; Kin Sing Stephen Lee Journal: J Lipid Res Date: 2018-09-12 Impact factor: 5.922