Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

Sumanta Kumar Goswami, Bora Inceoglu, Jun Yang, Debin Wan, Sean D. Kodani, Carlos Antonio Trindade da Silva, Christophe Morisseau, Bruce D. Hammock

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100mg/kg/day, p.o., 7days), sEH inhibitor TPPU (3mg/kg/day, p.o.) and OME (100mg/kg/day, p.o., 7days)+TPPU (3mg/kg/day, p.o., last 3days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE2 was monitored. While OME treatment by itself exhibited variable effects on PGE2 induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME+TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study.

Original languageEnglish (US)
Pages (from-to)419-427
Number of pages9
JournalToxicology and Applied Pharmacology
Volume289
Issue number3
DOIs
StatePublished - Dec 15 2015

Keywords

  • Cytochrome P450 1A
  • Epoxyeicosatrienoic acid
  • Omeprazole
  • Prostaglandin E induced hyperalgesia
  • SEH inhibitor TPPU
  • Time dependent P450 induction

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Fingerprint Dive into the research topics of 'Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE<sub>2</sub> induced pain model'. Together they form a unique fingerprint.

  • Cite this

    Goswami, S. K., Inceoglu, B., Yang, J., Wan, D., Kodani, S. D., da Silva, C. A. T., Morisseau, C., & Hammock, B. D. (2015). Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model. Toxicology and Applied Pharmacology, 289(3), 419-427. https://doi.org/10.1016/j.taap.2015.10.018