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.