4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1
4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1
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DOI：
10.1073/pnas.0705923104
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发表时间：
2007-08-14
影响因子：
11.1
通讯作者：
Geppetti, Pierangelo
中科院分区：
文献类型：
--
作者：
Trevisani, Marcello;Siemens, Jan;Geppetti, Pierangelo
TRPA 1是一种兴奋性离子通道，由含有P物质和降钙素基因相关肽的初级传入体感神经元亚群表达。芥子油、大蒜素和丙烯醛等环境刺激物激活TRPA 1，引起急性疼痛、神经肽释放和神经源性炎症。遗传学研究表明，TRPA 1也激活下游的一个或多个促痛剂，刺激磷脂酶C信号通路，从而牵连这一通道的外周机制控制疼痛超敏性。然而，目前尚不清楚组织损伤是否也产生内源性促痛因子，这些促痛因子直接激活TRPA 1以增加炎性疼痛。在这里，我们报告了重组或天然TRPA 1通道被4-羟基-2-壬烯醛（HNE）激活，4-羟基-2-壬烯醛（HNE）是一种内源性α，β-不饱和醛，当反应性氧自由基在组织损伤，炎症和氧化应激反应中过氧化膜磷脂时产生。HNE引起P物质和降钙素基因相关肽从中枢（脊髓）和外周（食管）神经末梢释放，导致外周组织中的神经源性血浆蛋白外渗。此外，将HNE注射到啮齿动物后爪中可诱发疼痛相关行为，该疼痛相关行为被TRPA 1拮抗剂抑制，并且在缺乏功能性TRPA 1通道的动物中不存在。这些发现表明，HNE激活伤害性神经元上的TRPA 1以促进急性疼痛、神经肽释放和神经源性炎症。我们的研究结果还为开发靶向HNE产生或TRPA 1激活的新型镇痛或抗炎药物提供了基于机制的理论基础。
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 hypersensitivity. 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 alpha,beta-unsaturated aidehyde 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.