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Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways.

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Title: Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways.
Authors: Inceoglu, Bora1, Jinks, Steven L.2, UIu, Arzu1, Hegedus, Christine M.1, Georgi, Katrin1, Schmelzer, Kara R.1, Wagner, Karen1, Jones, Paul D.1, Morisseau, Christophe1, Hammock, Bruce D.1 bdhammock@ucdavis.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 12/2/2008, Vol. 105 Issue 48, p18901-18906. 6p. 1 Diagram, 2 Graphs.
Subjects: Inflammation, Arachidonic acid, Cyclooxygenases, Prostaglandins, Cytochromes, Messenger RNA
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 (EEls) by cytochrome P450 enzymes. EET levels are typically regulated by soluble epoxide hydrolase (5EH), the major enzyme degrading EET5. Here we demonstrate that EET5 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 EEl 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 EET5 is a novel path to accomplish pain relief in both inflammatory and neuropathic pain states. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
Description
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 (EEls) by cytochrome P450 enzymes. EET levels are typically regulated by soluble epoxide hydrolase (5EH), the major enzyme degrading EET5. Here we demonstrate that EET5 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 EEl 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 EET5 is a novel path to accomplish pain relief in both inflammatory and neuropathic pain states. [ABSTRACT FROM AUTHOR]
ISSN:00278424
DOI:10.1073/pnas.0809765105