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Title: Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE{sub 2} induced pain model

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 (100 mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3 mg/kg/day, p.o.) and OME (100 mg/kg/day, p.o., 7 days) + TPPU (3 mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE{sub 2} was monitored. While OME treatment by itself exhibited variable effects on PGE{sub 2} 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 increasingmore » generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study. - Highlights: • The soluble epoxide hydrolase (sEH) inhibitor TPPU is anti-hyperalgesic. • Omeprazole potentiates the anti-hyperalgesic actions of TPPU. • This potentiation is associated with increased P450 activity. • The potentiation is associated with an increase in fatty acid epoxide/diol ratio. • Joint use of sEH inhibitors and P450 inducers could result in drug–drug interactions.« less

Authors:
; ; ; ;  [1];  [1];  [1]
  1. Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA (United States)
Publication Date:
OSTI Identifier:
22687847
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 289; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANALGESICS; ARACHIDONIC ACID; CATABOLISM; CYTOCHROMES; EPOXIDES; GLYCOLS; HYDROLASES; INFLAMMATION; INHIBITION; LIVER; METABOLITES; MICROSOMES; PAIN; PROSTAGLANDINS; RATS; SENSITIVITY; TIME DEPENDENCE

Citation Formats

Goswami, Sumanta Kumar, Inceoglu, Bora, Yang, Jun, Wan, Debin, Kodani, Sean D., Trindade da Silva, Carlos Antonio, Department of Genetics and Biochemistry, Federal University of Uberlandia, MG, Morisseau, Christophe, and Hammock, Bruce D., E-mail: bdhammock@ucdavis.edu. Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE{sub 2} induced pain model. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2015.10.018.
Goswami, Sumanta Kumar, Inceoglu, Bora, Yang, Jun, Wan, Debin, Kodani, Sean D., Trindade da Silva, Carlos Antonio, Department of Genetics and Biochemistry, Federal University of Uberlandia, MG, Morisseau, Christophe, & Hammock, Bruce D., E-mail: bdhammock@ucdavis.edu. Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE{sub 2} induced pain model. United States. doi:10.1016/J.TAAP.2015.10.018.
Goswami, Sumanta Kumar, Inceoglu, Bora, Yang, Jun, Wan, Debin, Kodani, Sean D., Trindade da Silva, Carlos Antonio, Department of Genetics and Biochemistry, Federal University of Uberlandia, MG, Morisseau, Christophe, and Hammock, Bruce D., E-mail: bdhammock@ucdavis.edu. Tue . "Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE{sub 2} induced pain model". United States. doi:10.1016/J.TAAP.2015.10.018.
@article{osti_22687847,
title = {Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE{sub 2} induced pain model},
author = {Goswami, Sumanta Kumar and Inceoglu, Bora and Yang, Jun and Wan, Debin and Kodani, Sean D. and Trindade da Silva, Carlos Antonio and Department of Genetics and Biochemistry, Federal University of Uberlandia, MG and Morisseau, Christophe and Hammock, Bruce D., E-mail: bdhammock@ucdavis.edu},
abstractNote = {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 (100 mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3 mg/kg/day, p.o.) and OME (100 mg/kg/day, p.o., 7 days) + TPPU (3 mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE{sub 2} was monitored. While OME treatment by itself exhibited variable effects on PGE{sub 2} 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. - Highlights: • The soluble epoxide hydrolase (sEH) inhibitor TPPU is anti-hyperalgesic. • Omeprazole potentiates the anti-hyperalgesic actions of TPPU. • This potentiation is associated with increased P450 activity. • The potentiation is associated with an increase in fatty acid epoxide/diol ratio. • Joint use of sEH inhibitors and P450 inducers could result in drug–drug interactions.},
doi = {10.1016/J.TAAP.2015.10.018},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 289,
place = {United States},
year = {2015},
month = {12}
}