Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents
Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents
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DOI：
10.1172/jci41678
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发表时间：
2010-05-01
影响因子：
15.9
通讯作者：
Hargreaves, Kenneth M.
中科院分区：
文献类型：
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作者：
Patwardhan, Amol M.;Akopian, Armen N.;Hargreaves, Kenneth M.
瞬时受体电位香草蛋白1 （TRPV1）通道是周围神经系统中主要的有害热探测器。TRPV1在许多伤害感受器中表达，并参与热致痛觉过敏和体温调节。介导TRPV1热敏性的确切机制尚不清楚。在这里，我们已经证明氧化亚油酸代谢物9-和13-羟基十八烯二烯酸（9-和13-HODE）在暴露于有毒热量的小鼠和大鼠皮肤活检中形成。9-和13-HODE及其代谢产物9-和13-oxoODE可激活TRPV1，因此构成了内源性TRPV1激动剂家族。此外，阻断这些物质可显著降低大鼠和小鼠TRPV1的热敏性，并减少伤害感觉。总之，我们的结果表明，HODEs有助于啮齿动物TRPV1的热敏性。由于氧化亚油酸代谢物在细胞损伤过程中释放，这些发现提示了一种整合TRPV1和亚油酸代谢物的致痛和促炎作用的机制，并可能为研究新型镇痛药物提供基础。
The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9- and 13-HODE and their metabolites, 9- and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs.