Nerve conduction block in cold-responsive sensory neurons

冷反应性感觉神经元的神经传导阻滞

基本信息

批准号：
9480110
负责人：
David D McKemy
金额：
$ 37.36万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9480110
关键词：
Acute Affect Afferent Neurons Agonist Anesthetics Animals Behavior Behavioral Biological Assay Cations Cells Charge Chronic Data Development Electrophysiology (science)Esthesia Fluorescent Dyes Hypersensitivity In Vitro Individual Inflammatory Injections Injury Ion Channel Lidocaine Local Anesthetics Mammals Mechanics Mediating Menthol Modality Motor Mus Nerve Nerve Block Neural Conduction Neurons Neuropathy Nociception Nociceptors Pain Pathology Permeability Pharmacology Phenotype Population Reporting Residual state Role Signal Pathway Signal Transduction Sodium Specificity TRPA1 Channel TRPV1 gene Time Whole-Cell Recordings base cell type channel blockers chronic pain efficacy testing experimental study genetic approach inflammatory neuropathic pain mouse model novel novel strategies pain behavior pain model pain relief perineural prevent public health relevance receptor response sensor somatosensory uptake voltage

项目摘要

DESCRIPTION (provided by applicant): The menthol receptor TRPM8 is considered the principal cold sensor in mammalian sensory neurons as animals lacking TRPM8 function are deficient in cold and cold pain behaviors. However some residual cold sensitivity remains, indicating the possible presence of TRPM8-independent cold transduction mechanisms. Other cell types, such as those expressing TRPV1 and TRPA1 channels, are critical for somatosensory signaling, and have been implicated in certain aspects of cold sensation. Genetic approaches to determine the role of these channels and cell-types are complicated by the fact that the resulting phenotypes are investigated either many days after manipulation, or in developmentally disparate backgrounds. An elegant approach has recently been devised that targets cell impermeant sodium (Na+) channel blockers to only primary sensory neurons mediating pain (nociceptors). Specifically, when stimulated with agonists for nociceptor-specific TRPV1 and TRPA1 channels, large molecules such as the charged lidocaine derivative QX-314 permeate through these channels, thereby selectively blocking nerve conduction in just these neuronal populations. Previous reports failed to find large molecule entry through TRPM8 channels, suggesting that TRPM8 neurons cannot be targeted in this manner. Our underlying hypothesis, supported by our novel preliminary data, is that large molecules permeate cells through TRPM8 when the channel is activated by potent agonists, and we propose to determine if cold and cold pain can be ameliorated by selectively blocking nerve conduction of these and other neuronal populations. Aim 1 will determine the mechanisms whereby TRPM8 channels permeate large cations in vitro and be used as a means to target Na+-channel blockers to TRPM8 neurons. Aim 2 will determine if targeting Na+-channel blockers in TRPM8 neurons alters cold sensation in mice, and determine if other primary sensory neurons also contribute to cold. Aim 3 will extend these behavioral analyses to determine if chronic cold pain induced by injury can be ameliorated by targeting Na+-channel blockers to TRPM8, TRPV1, or TRPA1 neurons. With these studies we will determine if cold and cold pain can be specifically inhibited by the selective entry of large, cell impermeant anesthetics, as well as use this novel approach to further define the cellular basis for cold and cold pain, including identifying TRPM8-independent neuronal populations that contribute to this somatosensory modality.

描述（申请人提供）：薄荷醇受体TRPM8被认为是哺乳动物感觉神经元中的主要冷感受器，因为缺乏TRPM8功能的动物缺乏冷和冷痛行为。然而，一些残余的冷敏感性仍然存在，表明可能存在不依赖TRPM8的冷传导机制。其他细胞类型，例如表达 TRPV1 和 TRPA1 通道的细胞，对于体感信号传导至关重要，并且与冷感的某些方面有关。确定这些通道和细胞类型的作用的遗传方法变得复杂，因为所产生的表型要么在操作后许多天进行研究，要么在发育不同的背景中进行研究。最近设计了一种优雅的方法，将细胞非渗透性钠 (Na+) 通道阻滞剂仅作用于介导疼痛的初级感觉神经元（伤害感受器）。具体来说，当用伤害感受器特异性 TRPV1 和 TRPA1 通道的激动剂刺激时，带电利多卡因衍生物 QX-314 等大分子会渗透到这些通道，从而选择性地阻断这些神经元群中的神经传导。之前的报道未能发现大分子通过 TRPM8 通道进入，这表明不能以这种方式靶向 TRPM8 神经元。我们的基本假设是，当TRPM8通道被强效激动剂激活时，大分子会通过TRPM8渗透细胞，并得到我们新的初步数据的支持，我们建议确定是否可以通过选择性阻断这些和其他通道的神经传导来改善冷痛和冷痛。神经元群。目标 1 将确定 TRPM8 通道在体外渗透大阳离子的机制，并用作将 Na+ 通道阻滞剂靶向 TRPM8 神经元的手段。目标 2 将确定 TRPM8 神经元中的 Na+ 通道阻滞剂是否会改变小鼠的冷感，并确定其他初级感觉神经元是否也会导致冷感。目标 3 将扩展这些行为分析，以确定是否可以通过将 Na+ 通道阻滞剂靶向 TRPM8、TRPV1 或 TRPA1 神经元来改善由损伤引起的慢性冷痛。通过这些研究，我们将确定是否可以通过选择性进入大的、不渗透细胞的麻醉剂来特异性抑制冷痛和冷痛，并使用这种新方法进一步定义冷痛和冷痛的细胞基础，包括识别不依赖于 TRPM8 的细胞基础。有助于这种体感模式的神经元群。