Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

Bora Inceoglu, Steven L. Jinks, Arzu Ulu, Christine M. Hegedus, Katrin Georgi, Kara R. Schmelzer, Karen Wagner, Paul D. Jones, Christophe Morisseau, Bruce D. Hammock

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

During inflammation, a large amount of arachidonic acid (AA) is released into the cellular milieu and cyclooxygenase enzymes convert this AA to prostaglandins that in turn sensitize pain pathways. However, AA is also converted to natural epoxyeicosatrienoic acids (EETs) by cytochrome P450 enzymes. EET levels are typically regulated by soluble epoxide hydrolase (sEH), the major enzyme degrading EETs. Here we demonstrate that EETs or inhibition of sEH lead to antihyperalgesia by at least 2 spinal mechanisms, first by repressing the induction of the COX2 gene and second by rapidly up-regulating an acute neurosteroid-producing gene, StARD1, which requires the synchronized presence of elevated cAMP and EET levels. The analgesic activities of neurosteroids are well known; however, here we describe a clear course toward augmenting the levels of these molecules. Redirecting the flow of pronociceptive intracellular cAMP toward up-regulation of StARD1 mRNA by concomitantly elevating EETs is a novel path to accomplish pain relief in both inflammatory and neuropathic pain states.

Original languageEnglish (US)
Pages (from-to)18901-18906
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number48
DOIs
StatePublished - Dec 2 2008

Keywords

  • cAMP
  • Inflammatory pain
  • Steroidogenesis

ASJC Scopus subject areas

  • General

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