Molecular Pain Mechanisms

描述(申请人提供)：我们建议研究一种新的感觉神经元检测伤害性刺激的机制。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、热和机械刺激是由伤害性感觉神经元表达的各种G蛋白偶联受体和离子通道传递的。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的治疗--这是最常被提及的医疗保健问题。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TRPV1，这是炎症性痛觉过敏发展所必需的离子通道。从这一观察中引出的一个重要问题是，碱性多肽是否可以类似地调节TRPV1的功能，从而调节感觉神经的兴奋性。免疫细胞和上皮细胞分泌一系列高电荷的阳离子蛋白质和多肽。重要的是，这些阳离子的水平在炎症组织中显著升高，然而，尽管有这种观察，它们对感觉神经功能的影响几乎没有被探索过。我们假设聚阳离子和阳离子多肽可以通过调节TRPV1来调节伤害性感受器的兴奋性。我们将使用强大的电生理学和生化方法的组合来验证这一创新假设：在目标1中，我们将确定几种炎症性阳离子多肽/蛋白质对TRPV1的激活和敏化。在目标2中，我们将探索多胺和阳离子多肽触发感觉神经准备的外周和中央终末神经肽分泌的能力。在目标3中，我们计划确定由TRPV1的阳离子调节引起的伤害性行为和病理。

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.