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Down‐regulation of CNS cyclooxygenase‐2 message by inhibitors of soluble epoxide hydrolase lead to anti‐hyperalgesia in inflammatory pain
Author(s) -
Inceoglu Bora,
Ulu Arzu,
Hegedus Christine,
Georgi Katrin,
Jinks Steve L.,
Hammock Bruce D.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.479.18
Subject(s) - epoxide hydrolase 2 , chemistry , cyclooxygenase , pharmacology , hyperalgesia , inflammation , arachidonic acid , epoxide hydrolase , prostaglandin e2 , prostaglandin , cytochrome p450 , biochemistry , enzyme , medicine , nociception , receptor , microsome
Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid produced by cytochrome P450s, have recently been shown to possess anti‐inflammatory and anti‐hyperalgesic activities. Through inhibition of soluble epoxide hydrolase (sEH), the major enzyme that inactivates these metabolites, we have shown that plasma concentrations and residence times of EETs can be increased dramatically. Interestingly, in models of inflammation, inhibition of sEH leads to decreases in circulating pro‐inflammatory lipid mediator concentrations, most prominently prostaglandin E2. We previously showed that sEH inhibitors transcriptionally down‐regulate cyclooxygenase (COX2) message in mouse liver. Indeed co‐administration of sEH inhibitors and selective COX‐2 inhibitors lead to a synergistic reduction in circulating prostaglandin concentrations. Here we show that the analgesic potency of inhibitors of sEH are comparable to that of morphine and that sEH inhibitors penetrate the blood brain barrier and down‐regulate the spinal induction of COX2 mRNA in response to peripheral local inflammation.