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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1
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4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1

机译：4-羟基壬醛，一种内源性醛，通过刺激刺激性受体TRPA1引起疼痛和神经性炎症

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摘要

TRPA1 is an excitatory ion channel expressed by a subpopulation of primary afferent somatosensory neurons that contain substance P and calcitonin gene-related peptide. Environmental irritants such as mustard oil, allicin, and acrolein activate TRPA1, causing acute pain, neuropeptide release, and neurogenic inflammation. Genetic studies indicate that TRPA1 is also activated downstream of one or more proalgesic agents that stimulate phospholipase C signaling pathways, thereby implicating this channel in peripheral mechanisms controlling pain hypersensi-tivity. However, it is not known whether tissue injury also produces endogenous proalgesic factors that activate TRPA1 directly to augment inflammatory pain. Here, we report that recombinant or native TRPA1 channels are activated by 4-hydroxy-2-nonenal (HNE), an endogenous α,β-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by TRPA1 antagonists and absent in animals lacking functional TRPA1 channels. These findings demonstrate that HNE activates TRPA1 on nociceptive neurons to promote acute pain, neuropeptide release, and neurogenic inflammation. Our results also provide a mechanism-based rationale for developing novel analgesic or anti-inflammatory agents that target HNE production or TRPA1 activation.
机译：TRPA1是一种兴奋性离子通道，由包含P物质和降钙素基因相关肽的初级传入体感神经元的亚群表达。环境刺激物，例如芥子油，大蒜素和丙烯醛会激活TRPA1，从而导致急性疼痛，神经肽释放和神经源性炎症。遗传研究表明，TRPA1在刺激磷脂酶C信号传导途径的一种或多种镇痛药的下游也被激活，从而将此通道牵涉到控制疼痛超敏反应的外围机制中。但是，尚不清楚组织损伤是否还会产生直接激活TRPA1以加剧炎症性疼痛的内源性镇痛因子。在这里，我们报道重组或天然TRPA1通道被4-羟基-2-壬烯醛（HNE）激活，这是一种内源性α，β-不饱和醛，当活性氧过氧化膜磷脂响应组织损伤，炎症，和氧化应激。 HNE引起中枢神经（脊髓）和外周神经（食道）末端释放P物质和降钙素基因相关肽，导致外周组织神经源性血浆蛋白外渗。此外，将HNE注入啮齿动物后爪会引起疼痛相关行为，该行为被TRPA1拮抗剂抑制，而在缺乏功能性TRPA1通道的动物中则不存在。这些发现表明，HNE可激活伤害性神经元上的TRPA1，从而促进急性疼痛，神经肽释放和神经源性炎症。我们的结果还为开发靶向HNE产生或TRPA1活化的新型镇痛药或抗炎药提供了基于机理的原理。

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