title: Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE₂ 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 (100mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3mg/kg/day, p.o.) and OME (100mg/kg/day, p.o., 7 days)+TPPU (3mg/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 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.
authors.affiliation: Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Sumanta Kumar
authors.initials: SK
authors.lastname: Goswami
authors.affiliation: Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Debin
authors.initials: D
authors.lastname: Wan
authors.affiliation: Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Kodani
authors.affiliation: Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA; Department of Genetics and Biochemistry, Federal University of Uberlandia, MG, Brazil.
authors.forename: Carlos Antonio Trindade
authors.initials: CA
authors.lastname: da Silva
authors.affiliation: Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA. Electronic address: bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology*; D006930:Hyperalgesia / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D000700:Analgesics; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D010671:Phenylurea Compounds; D010880:Piperidines; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases; D015232:Dinoprostone; D009853:Omeprazole
keywords: Cytochrome P450 1A; Epoxyeicosatrienoic acid; Omeprazole; Prostaglandin E(2) induced hyperalgesia; Time dependent P450 induction; sEH inhibitor TPPU