Molecular Pain Mechanisms

描述（由申请人提供）：我们提出研究一种新的机制，通过这种机制，感觉神经元检测伤害性刺激。检测有害刺激的能力对生存至关重要，但也可能是不必要的疼痛的来源。伤害性化学、热和机械刺激通过伤害性感觉神经元中表达的多种G蛋白偶联受体和离子通道转导。这些神经元中的信号通路无疑是复杂的，但破译这些通路有望改善疼痛治疗的潜力-最常被引用的医疗保健问题。一种新发现的有害信号模式是通过阳离子的静电荷发生的。细胞外阳离子和多胺可以直接敏化和门控辣椒素受体TRPV 1，一种对炎症性痛觉过敏的发展至关重要的离子通道。从这一观察中产生的一个重要问题是碱性肽是否可以类似地调节TRPV 1的功能，从而调节感觉神经的兴奋性。免疫和上皮细胞分泌一系列高度带电的阳离子蛋白质和肽。重要的是，这些阳离子的水平在发炎组织中显著升高，然而，尽管有这种观察结果;它们对感觉神经功能的影响几乎没有被探索过。我们推测聚阳离子和阳离子肽可以通过调节TRPV 1来调节伤害感受器的兴奋性。我们将使用强大的电生理学和生物化学方法的组合来测试这一创新假设：在目标1中，我们将确定几种炎性阳离子肽/蛋白对TRPV 1的激活和致敏作用。在目标2中，我们将探讨多胺和阳离子肽触发感觉神经制备物的外周和中枢末端的神经肽分泌的能力。在目标3中，我们计划确定TRPV 1的阳离子调节引起的伤害性行为和病理学。

DESCRIPTION (provided by applicant): We propose to study a novel mechanism by which sensory neurons detect noxious stimuli. The ability to detect noxious stimuli is critical to survival, but can also be the source of unwanted pain. Injurious chemical, thermal and mechanical stimuli are transduced by a variety of G-protein coupled receptors and ion channels expressed in nociceptive sensory neurons. The signaling pathways in these neurons are undoubtedly complex, but deciphering these pathways promises the potential for improved treatment of pain-the most frequently cited health-care concern. One newly identified mode of noxious signaling occurs via the electrostatic charge of cations. Extracellular cations and polyamines can directly sensitize and gate the capsaicin receptor TRPV1, an ion channel essential for the development of inflammatory hyperalgesia. An important question arising from this observation is whether basic peptides can similarly modulate the function of TRPV1 and thereby regulate sensory nerve excitability. Immune and epithelial cells secrete an array of highly charged, cationic proteins and peptides. Importantly, levels of these cations are markedly elevated in inflamed tissue, however despite this observation; their effects on sensory nerve function have barely been explored. We hypothesize that polycations and cationic peptides can regulate the excitability of nociceptors through the modulation of TRPV1. We will test this innovative hypothesis using a combination of robust electrophysiological and biochemical methodologies: In Aim 1 we will determine the activation and sensitization of TRPV1 by several inflammatory cationic peptides/proteins. In Aim 2 we will explore the ability of polyamines and cationic peptides to trigger neuropeptide secretion from peripheral and central terminals of sensory nerve preparations. In Aim 3 we plan to identify nociceptive behaviors and pathology arising from cationic regulation of TRPV1.