Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP

Bora Inceoglu, Karen Wagner, Nils H. Schebb, Christophe Morisseau, Steven L. Jinks, Arzu Ulu, Christine Hegedus, Tristan Rose, Robert J Brosnan, Bruce D. Hammock

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Pain is a major health concern even though numerous analgesic agents are available. Side effects and lack of wide-spectrum efficacy of current drugs justify efforts to better understand pain mechanisms. Stabilization of natural epoxy-fatty acids (EFAs) through inhibition of the soluble epoxide hydrolase (sEH) reduces pain. However, in the absence of an underlying painful state, inhibition of sEH is ineffective. Surprisingly, a pain-mediating second messenger, cAMP, interacts with natural EFAs and regulates the analgesic activity of sEH inhibitors. Concurrent inhibition of sEH and phosphodiesterase (PDE) dramatically reduced acute pain in rodents. Our findings demonstrate a mechanism of action of cAMP and EFAs in the pathophysiology of pain. Furthermore, we demonstrate that inhibition of various PDE isozymes, including PDE4, lead to significant increases in EFA levels through a mechanism independent of sEH, suggesting that the efficacy of commercial PDE inhibitors could result in part from increasing EFAs. The cross-talk between the two major pathways - one mediated by cAMP and the other by EFAs - paves the way to new approaches to understand and control pain.

Original languageEnglish (US)
Pages (from-to)5093-5097
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number12
DOIs
StatePublished - Mar 22 2011

Keywords

  • Antinociceptive
  • Epoxyeicosatrienoic acid
  • Nociception

ASJC Scopus subject areas

  • General

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    Inceoglu, B., Wagner, K., Schebb, N. H., Morisseau, C., Jinks, S. L., Ulu, A., Hegedus, C., Rose, T., Brosnan, R. J., & Hammock, B. D. (2011). Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP. Proceedings of the National Academy of Sciences of the United States of America, 108(12), 5093-5097. https://doi.org/10.1073/pnas.1101073108