Goswami Sumanta Kumar, Inceoglu Bora, Yang Jun, Wan Debin, Kodani Sean D, da Silva Carlos Antonio Trindade, Morisseau Christophe, Hammock Bruce D
Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA.
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.
Toxicol Appl Pharmacol. 2015 Dec 15;289(3):419-27. doi: 10.1016/j.taap.2015.10.018. Epub 2015 Nov 10.
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.
环氧二十碳三烯酸（EETs）是细胞色素P450（P450s）由花生四烯酸产生的强效内源性镇痛代谢产物。可溶性环氧化物水解酶（sEH）对EETs的代谢会降低其活性，而通过抑制sEH来稳定EETs则可减轻炎症性疼痛和神经性疼痛。在此，我们验证了一个补充假说，即通过奥美拉唑（OME）诱导P450s来提高EETs水平，其本身可影响疼痛相关信号传导，并增强sEH抑制剂的抗痛觉过敏作用。将大鼠用溶解于聚乙二醇400（PEG400）的OME（100mg/kg/天，口服，7天）、sEH抑制剂TPPU（3mg/kg/天，口服）以及OME（100mg/kg/天，口服，7天）+TPPU（3mg/kg/天，口服，在OME给药的最后3天）进行处理，并监测它们对前列腺素E2（PGE2）诱导的痛觉过敏（对疼痛敏感性增加）的影响。虽然单独使用OME处理对PGE2诱导的痛觉过敏表现出不同的影响，但在同一实验中它强烈增强了TPPU的作用。OME+TPPU处理后疼痛的显著减轻与血浆中EETs水平的升高以及肝微粒体中P450 1A1和P450 1A2活性的增加相关。结果表明，用sEH抑制剂减少EETs的分解代谢比通过OME增加EETs的生成产生更强的镇痛效果，并且在本研究条件下两者联合使用产生最强的疼痛减轻效果。
