Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors

Kara R. Schmelzer, Bora Inceoglu, Lukas Kubala, In Hae Kim, Steven L. Jinks, Jason P. Eiserich, Bruce D. Hammock

Research output: Contribution to journalArticlepeer-review

153 Scopus citations


Combination therapies have long been used to treat inflammation while reducing side effects. The present study was designed to evaluate the therapeutic potential of combination treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and previously undescribed soluble epoxide hydrolase inhibitors (sEHIs) in lipopolysaccharide (LPS)-challenged mice. NSAIDs inhibit cyclooxygenase (COX) enzymes and thereby decrease production of metabolites that lead to pain and inflammation. The sEHIs, such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), stabilize anti-inflammatory epoxy-eicosatrienoic acids, which indirectly reduce the expression of COX-2 protein. Here we demonstrate that the combination therapy of NSAIDs and sEHIs produces significantly beneficial effects that are additive for alleviating pain and enhanced effects in reducing COX-2 protein expression and shifting oxylipin metabolomic profiles. When administered alone. AUDA-BE decreased protein expression of COX-2 to 73 ± 6% of control mice treated with LPS only without altering COX-1 expression and decreased PGE2 levels to 52 ± 8% compared with LPS-treated mice not receiving any therapeutic intervention. When AUDA-BE was used in combination with low doses of indomethacin, celecoxib, or rofecoxib, PGE2 concentrations dropped to 51 ± 7, 84 ± 9, and 91 ± 8%, respectively, versus LPS control, without disrupting prostacyclin and thromboxane levels. These data suggest that these drug combinations (NSAIDs and sEHIs) produce a valuable beneficial analgesic and anti-inflammatory effect while prospectively decreasing side effects such as cardiovascular toxicity.

Original languageEnglish (US)
Pages (from-to)13646-13651
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 12 2006


  • Arachidonic acid
  • Cyclooxygenase
  • Epoxygenase
  • Linoleic acid
  • Pain

ASJC Scopus subject areas

  • Genetics
  • General


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