Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia
Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia
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DOI：
10.1073/pnas.0905415106
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发表时间：
2009-11-03
影响因子：
11.1
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.;Scotland, Phoebe E.;Hargreaves, Kenneth M.
瞬时受体电位香草酸1（TRPV 1）在痛觉过敏和异常性疼痛中起主要作用，并且在外周和中枢神经系统（CNS）中表达。然而，很少有研究评估中枢神经系统TRPV 1介导损伤后痛觉过敏和异常性疼痛的机制。我们假设脊髓系统的激活释放内源性TRPV 1激动剂，通过该受体引起机械性异常性疼痛的发展。使用体外灌流，脊髓的去极化触发了氧化亚油酸代谢物的释放，例如9-羟基十八碳二烯酸（9-HODE），其有效地激活脊髓TRPV 1，导致机械性异常性疼痛的发展。随后的钙成像和电生理学研究表明，合成的氧化亚油酸代谢产物，包括9-HODE，13-HODE，9和13-oxoODE，组成了一个内源性TRPV 1激动剂家族。体内研究表明，鞘内应用这些氧化亚油酸代谢物可迅速引起机械性异常性疼痛。最后，通过抗体鞘内中和9-和13-HODE阻断CFA诱发的机械性异常性疼痛。这些数据共同揭示了一种机制，通过这种机制，内源性脂质家族激活脊髓中的TRPV 1，导致炎症性痛觉过敏的发展。这些发现可能整合了许多疼痛疾病，并为开发镇痛药物提供了一种方法。
Transient receptor potential vanilloid 1 (TRPV1) plays a major role in hyperalgesia and allodynia and is expressed both in the peripheral and central nervous systems (CNS). However, few studies have evaluated mechanisms by which CNS TRPV1 mediates hyperalgesia and allodynia after injury. We hypothesized that activation of spinal cord systems releases endogenous TRPV1 agonists that evoke the development of mechanical allodynia by this receptor. Using in vitro superfusion, the depolarization of spinal cord triggered the release of oxidized linoleic acid metabolites, such as 9-hydroxyoctadecadienoic acid (9-HODE) that potently activated spinal TRPV1, leading to the development of mechanical allodynia. Subsequent calcium imaging and electrophysiology studies demonstrated that synthetic oxidized linoleic acid metabolites, including 9-HODE, 13-HODE, and 9 and 13-oxoODE, comprise a family of endogenous TRPV1 agonists. In vivo studies demonstrated that intrathecal application of these oxidized linoleic acid metabolites rapidly evokes mechanical allodynia. Finally, intrathecal neutralization of 9- and 13-HODE by antibodies blocks CFA-evoked mechanical allodynia. These data collectively reveal a mechanism by which an endogenous family of lipids activates TRPV1 in the spinal cord, leading to the development of inflammatory hyperalgesia. These findings may integrate many pain disorders and provide an approach for developing analgesic drugs.