Molecular and cellular mechanisms of cold allodynia

冷异常性疼痛的分子和细胞机制

• 批准号: 10198050
• 负责人: David D McKemy
• 金额: $ 36.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198050
• 关键词: Ablation; Absence of pain sensation; Acute; Address; Afferent Neurons; Antipruritics; Behavior; Behavioral; Candidate Disease Gene; Cells; Detection; Esthesia; Genetic; Health; Hypersensitivity; Inflammatory; Injury; Irritants; Knock-out; Knowledge; Label; Ligands; Mediating; Mediator of activation protein; Menthol; Modality; Modeling; Molecular; Mus; Nervous system structure; Neurons; Neuropathy; Pain; Pathologic; Pathology; Pathway interactions; Phenotype; Physiological; Play; Role; Signal Transduction; Signal Transduction Pathway; Stimulus; TRPA channel; Temperature; Testing; Transgenic Mice; allodynia; behavioral pharmacology; cold temperature; conditional knockout; glial cell-line derived neurotrophic factor; in vivo; inflammatory pain; neural circuit; neuronal excitability; pain behavior; painful neuropathy; preference; receptor; response; sensor; somatosensory

Project Summary The detection of external stimuli such as temperature is critical for survival, yet inappropriate responses to temperature do have a significant negative impact on overall health. The sensations and the physiological effects of cold are distinct among somatosensory modalities in that cold provides a pleasant, soothing sensation at mild temperatures, but is also agonizing as temperatures decrease. Remarkably, how this one somatosensory modality mediates this diverse range of physiological effects is not known. The menthol receptor TRPM8 is considered the principal cold sensor in mammalian sensory neurons, but the irritant receptor TRPA1 have also been associated with cold pain. Mice lacking TRPM8 channels retain some limited cold sensitivity, but we find that ablation of TRPM8-expressing neurons in mice abolishes essentially all acute cold and cold pain behaviors, results implying TRPM8-independent cold transduction mechanisms in TRPM8+ neurons. TRPA1 channels appear to serve no role in acute cold, but likely contribute to injury-induced cold pain. TRPM8 and TRPA1 are not co-expressed, yet the interplay between TRPA1 and TRPM8 after injury has not been examined, nor have the molecular and cellular mechanisms leading to injury-induced sensitization. Recently, we found that the glial cell-line derived neurotrophic factor-like (GDNF) ligand artemin is a mediator of TRPM8-dependent cold pain, and that the artemin receptor GFRα3 is required for pathological cold allodynia. However, the molecular and cellular mechanisms whereby this pathway leads to cold allodynia is not known. Here we propose to use a combination of molecular, cellular, behavioral, and pharmacological approaches to fill in these gaps in our knowledge of the mechanisms underlying cold sensation. First, we will determine the role of TRPM8 and TRPA1 channels in cold allodynia. Second, we define the cellular basis for artemin-induced cold hypersensitivity. Third, we will test the necessity of the classical GFRα co-receptor Ret in cold allodynia and determine if other candidate co-receptors mediate this form of pathology. Lastly, we will generate transgenic mice in which genetically defined subpopulations of TRPM8 neurons are conditionally ablated in vivo to determine if innocuous cool, noxious cold, and analgesia are mediated cell autonomously. At the conclusion of these studies, we will have defined a signal transduction pathway leading to cold pain, and if these stimuli are transmitted via distinct neural circuits to mediate the range of behavioral and physiological responses to cold temperatures.

项目摘要 检测外部刺激（如温度）对生存至关重要，但对 温度确实对整体健康有显著负面影响。感觉和生理 冷的影响在躯体感觉方式中是不同的，因为冷提供了一种愉快的、舒缓的感觉。 在温和的温度下会有疼痛感，但随着温度的降低也会感到痛苦。值得注意的是，这一个 躯体感觉形态介导这种不同范围的生理效应是未知的。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，但刺激物TRPM 8是一种刺激性的冷传感器。 受体TRPA 1也与冷痛有关。缺乏TRPM 8通道的小鼠保留了一些有限的 冷敏感性，但我们发现，在小鼠中TRPM 8表达神经元的消融基本上消除了所有急性 冷和冷痛行为，结果表明TRPM 8+中TRPM 8-独立的冷转导机制 神经元TRPA 1通道似乎在急性感冒中没有作用，但可能有助于损伤诱导的感冒 痛苦TRPM 8和TRPA 1并不共表达，但损伤后TRPA 1和TRPM 8之间的相互作用， 尚未研究导致损伤诱导致敏的分子和细胞机制。 最近，我们发现胶质细胞源性神经营养因子样（GDNF）配体artemin是一种介导 TRPM 8依赖性冷痛，而artemin受体GFRα3是病理性冷痛所必需的。 异常性疼痛然而，该途径导致冷异常性疼痛的分子和细胞机制并不清楚。 知道的在这里，我们建议使用分子，细胞，行为和药理学的组合 填补我们对冷感觉机制的知识空白的方法。一是 确定TRPM 8和TRPA 1通道在冷异常性疼痛中的作用。其次，我们定义了细胞基础， 青蒿素诱导的冷过敏。第三，我们将测试经典GFRα共受体Ret在 冷异常性疼痛，并确定是否有其他候选共受体介导这种形式的病理。最后，我们将 产生转基因小鼠，其中TRPM 8神经元的遗传限定的亚群被条件性地 体内消融以确定无害的冷、有害的冷和镇痛是否是细胞自主介导的。在 这些研究的结论，我们将确定一个信号转导通路导致冷痛，如果 这些刺激通过不同的神经回路传递，以调节行为和生理的范围。 对低温的反应。