Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Erlangen, Germany.
Neuropeptides. 2011 Dec;45(6):391-400. doi: 10.1016/j.npep.2011.07.011. Epub 2011 Aug 24.
Vagal sensory afferents innervating airways and abdominal tissues express TRPV1 and TRPA1, two depolarizing calcium permeable ion channels playing a major role in sensing environmental irritants and endogenous metabolites which cause neuropeptide release and neurogenic inflammation. Here we have studied axonal chemosensitivity and control of neuropeptide release from the isolated rat and mouse vagus nerve by using prototypical agonists of these transduction channels - capsaicin, mustard oil and the specific endogenous activators, anandamide (methyl arachidonyl ethanolamide, mAEA), and acrolein, respectively. Capsaicin evoked iCGRP release from the rat vagus nerve with an EC₅₀ of 0.12 μM. Co-application of mAEA had a dual effect: nanomolar concentrations of mAEA (0.01 μM) significantly reduced capsaicin-evoked iCGRP release while concentrations ≥ 1 μM mAEA had sensitizing effects. Only 100 μM mAEA directly augmented iCGRP release by itself. In the mouse, 310 μM mAEA increased release in wildtype and TRPA1-/- mice which could be inhibited by capsazepine (10 μM) and was completely absent in TRPV1-/- mice. CB1-/- and CB1/CB2 double -/- mice equally displayed increased sensitivity to mAEA (100 μM) and a sensitizing effect to capsaicin, in contrast to wildtypes. Acrolein and mustard oil (MO)--at μM concentrations--induced a TRPA1-dependent iCGRP release; however, millimolar concentrations of mustard oil (>1mM) evoked iCGRP release by activating TRPV1, confirming recent evidence for TRPV1 agonism of high mustard oil concentrations. Taken together, we present evidence for functional expression of excitatory TRPV1, TRPA1, and inhibitory CB1 receptors along the sensory fibers of the vagus nerve which lend pathophysiological relevance to the axonal membrane and the control of neuropeptide release that may become important in cases of inflammation or neuropathy. Sensitization and possible ectopic discharge may contribute to the development of autonomic dysregulation in visceral tissues that are innervated by the vagus nerve.
支配气道和腹部组织的迷走感觉传入纤维表达 TRPV1 和 TRPA1，这两种去极化钙通透性离子通道在感知环境刺激物和内源性代谢物方面发挥着重要作用，这些物质会导致神经肽释放和神经源性炎症。在这里，我们使用这些转导通道的原型激动剂——辣椒素、芥末油和特定的内源性激活剂，即花生四烯酸甲酰乙醇酰胺（甲基花生四烯酸乙醇酰胺，mAEA）和丙烯醛，研究了分离的大鼠和小鼠迷走神经的轴突化学敏感性和神经肽释放的控制。辣椒素引起大鼠迷走神经中 iCGRP 释放的 EC₅₀为 0.12 μM。mAEA 的共应用具有双重作用：纳摩尔浓度的 mAEA（0.01 μM）显著降低辣椒素诱导的 iCGRP 释放，而浓度≥1 μM 的 mAEA 则具有敏化作用。只有 100 μM 的 mAEA 本身就能直接增加 iCGRP 释放。在小鼠中，310 μM 的 mAEA 增加了野生型和 TRPA1-/- 小鼠中的释放，这种释放可以被辣椒素（10 μM）抑制，并且在 TRPV1-/- 小鼠中完全不存在。CB1-/- 和 CB1/CB2 双重 -/- 小鼠对 mAEA（100 μM）同样表现出更高的敏感性，并且对辣椒素具有敏化作用，与野生型相比。丙烯醛和芥末油（MO）——在 μM 浓度下——诱导依赖于 TRPA1 的 iCGRP 释放；然而，毫摩尔浓度的芥末油（>1mM）通过激活 TRPV1 引起 iCGRP 释放，这证实了最近关于高芥末油浓度对 TRPV1 激动作用的证据。总之，我们提供了证据表明兴奋性 TRPV1、TRPA1 和抑制性 CB1 受体沿迷走神经感觉纤维表达，这使轴突膜和神经肽释放的控制具有病理生理学意义，这可能在炎症或神经病变的情况下变得重要。敏化和可能的异位放电可能导致受迷走神经支配的内脏组织自主功能失调的发展。
