Nerve conduction block in cold-responsive sensory neurons

冷反应性感觉神经元的神经传导阻滞

• 批准号: 8848153
• 负责人: David D McKemy
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848153
• 关键词: Affect; Afferent Neurons; Agonist; Anesthetics; Animals; Behavior; Behavioral; Biological Assay; Cations; Cells; Charge; Chronic; Data; Esthesia; Fluorescent Dyes; Health; Heating; Hypersensitivity; In Vitro; Inflammatory; Injection of therapeutic agent; Injury; Ion Channel; Lidocaine; Local Anesthetics; Mammals; Mechanics; Mediating; Menthol; Modality; Modeling; Motor; Mus; Nerve; Nerve Block; Neural Conduction; Neurons; Neuropathy; Nociception; Nociceptors; Pain; Pathology; Permeability; 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; genetic approach; inflammatory neuropathic pain; mouse model; novel; novel strategies; pain behavior; perineural; prevent; receptor; research study; response; sensor; somatosensory; uptake; voltage

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（由申请人提供）：薄荷醇受体TRPM 8被认为是哺乳动物感觉神经元中的主要冷传感器，因为缺乏TRPM 8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TRPM 8独立的冷转导机制。其他细胞类型，如表达TRPV 1和TRPA 1通道的细胞，对体感信号传导至关重要，并与冷感觉的某些方面有关。确定这些通道和细胞类型的作用的遗传学方法是复杂的，因为所产生的表型在操作后许多天或在发育上不同的背景下进行研究。最近设计了一种优雅的方法，将细胞不渗透性钠（Na+）通道阻滞剂仅靶向介导疼痛的初级感觉神经元（伤害感受器）。具体地，当用伤害感受器特异性TRPV 1和TRPA 1通道的激动剂刺激时，大分子如带电的利多卡因衍生物QX-314渗透通过这些通道，从而选择性地阻断仅在这些神经元群体中的神经传导。以前的报道未能发现大分子通过TRPM 8通道进入，这表明TRPM 8神经元不能以这种方式靶向。我们的基本假设，我们的新的初步数据支持，是大分子渗透细胞通过TRPM 8时，通道被激活的有效激动剂，我们建议确定是否可以通过选择性阻断这些和其他神经元群体的神经传导冷和冷痛得到改善。目的1将确定TRPM 8通道在体外渗透大阳离子的机制，并将其用作将Na+通道阻断剂靶向TRPM 8神经元的手段。目的2将确定靶向TRPM 8神经元中的Na+通道阻滞剂是否改变小鼠的冷感觉，并确定其他初级感觉神经元是否也有助于冷。目的3将扩展这些行为分析，以确定是否可以通过靶向TRPM 8，TRPV 1或TRPA 1神经元的Na+通道阻滞剂来改善损伤诱导的慢性冷痛。通过这些研究，我们将确定寒冷和冷痛是否可以通过选择性进入大的，细胞不渗透的麻醉剂来特异性抑制，以及使用这种新方法来进一步定义寒冷和冷痛的细胞基础，包括识别TRPM 8独立的神经元群体，这些神经元群体有助于这种躯体感觉方式。