Real-time imaging of skeletal muscle innervating sensory neurons that signal pain and fatigue

骨骼肌支配感觉神经元的实时成像，发出疼痛和疲劳信号

• 批准号: 10448425
• 负责人: Charles Jeffery WOODBURY
• 金额: $ 47.97万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448425
• 关键词: Ache; Acute Pain; Affect; Afferent Neurons; Attention; Blood flow; Bone structure; Brain; Cell Culture Techniques; Cells; Chemicals; Chemosensitization; Chronic; Chronic Disease; Chronic Fatigue Syndrome; Chronic Obstructive Pulmonary Disease; Clinical; Cognitive; Cutaneous; Diabetes Mellitus; Disease; Esthesia; Fatigue; Fibromyalgia; Goals; Headache Disorders; Heart failure; Image; Location; Lupus; Lymphatic Diseases; Malignant Neoplasms; Mechanical Stimulation; Mechanics; Mechanoreceptors; Mediator of activation protein; Medical Care Costs; Methods; Molecular; Mus; Muscle; Muscle Contraction; Muscle Fatigue; Myalgia; Myofascial Pain Syndromes; Nature; Nerve; Nerve Endings; Neurons; Nociception; Nociceptors; Pain; Peripheral; Peripheral Vascular Diseases; Persons; Preparation; Property; Protons; Research; Sensory; Signal Pathway; Signal Transduction; Skeletal Muscle; Spinal Ganglia; Stimulus; Symptoms; Technology; Temporomandibular Joint Disorders; Tension Headache; Time; Transgenic Mice; base; chronic painful condition; comorbidity; cost; disabling symptom; effective therapy; human subject; imaging modality; in vivo; mechanical force; mouse model; novel; optical imaging; pain perception; pain signal; real-time images; response; sensorimotor system; sensory mechanism; tool; translational study; trigger point

Muscle pain and fatigue affect nearly all people at some time in their lives. At present, effective treatments for short term muscle pain are clearly inadequate and adequate treatment for chronic muscle pain is even worse. Considerable evidence indicates that peripheral sensory dysregulation of group III/IV muscle afferents, and autonomic dysregulation may cause or contribute to both short-term and chronic muscle pain and fatigue.Our long term goal is to determine the fundamental mechanisms that signal intense muscle pain, ache and fatigue to sensory and motor systems. We have previously used discoveries in mouse models to prove that combinations of protons, lactate, and ATP are necessary and sufficient to activate muscle sensory neurons. In translational studies in human subjects we showed that combination of these three metabolites activated the sensations of muscle ache and fatigue in human subjects. We propose here to use several transgenic mice that will make it possible, for the first time, to determine the molecular, cellular, and structural mechanisms of the sensory signaling pathways for the cognitive sensations of muscle pain and muscle fatigue. These mice will also make it possible for us to determine the many different types of afferents that selectively signal the many different aspects of autonomic function that allow us to function over a wide range of muscle blood flow. Finally, these mice will make it possible for us to directly image not only the cell bodies of the muscle innervating neurons, but to directly observe the activation of the nerve endings in skeletal muscles by both metabolites and mechanical stimulation. These images may allow us to determine the mechanisms for “trigger points”, the pulsating nature of muscle ache, lymphatic disease associated with muscle fatigue and pain, and sympathetic activation of enhanced muscle pain. The specific aims of this proposal are: Aim 1: Define the different types of mechanosensitive, and metabosensitive sensory neurons innervating skeletal muscle based on their responses to muscle contraction. Aim 2: Determine if chemical mediators produced during muscle contraction are responsible for the potentiation seen among a subset of mechanosensitive muscle sensory neurons during muscle contraction. Aim 3: Determine if metaboreceptors and metabo-nociceptors also respond to mechanical forces generated during muscle contraction. Aim 4: Determine the location and structure of skeletal muscle sensory neurons signaling pain and fatigue via direct imaging of neuron terminals.

肌肉疼痛和疲劳在生活中几乎会影响所有人。目前，有效的治疗方法 短期肌肉疼痛显然不足，慢性肌肉疼痛的适当治疗甚至更糟。 大量证据表明，III/IV肌的外围感觉失调，以及 自主性失调可能会导致或导致短期和慢性肌肉疼痛和疲劳。 长期目标是确定信号强烈的肌肉疼痛，疼痛和疲劳的基本机制 到感官和运动系统。我们以前曾在鼠标模型中使用发现来证明 质子，鞋底和ATP的组合是必要的，足以激活肌肉感觉神经元。在 人类受试者的翻译研究我们表明，这三种代谢物的组合激活了 人类受试者的肌肉疼痛和疲劳的感觉。我们在这里建议使用几只转基因小鼠 这将使首次确定分子，细胞和结构机制 肌肉疼痛和肌肉疲劳的认知感觉的感觉信号通路。这些老鼠 还将使我们能够确定许多不同类型的传入，这些传入有选择地向 自主功能的许多不同方面，使我们能够在各种肌肉血流中发挥作用。 最后，这些小鼠将使我们不仅可以直接成像肌肉的细胞体 神经神经元，但直接观察骨骼肌肉中神经末端的激活 代谢物和机械刺激。这些图像可能使我们能够确定“触发”的机制 点”，肌肉疼痛的脉动性质，与肌肉疲劳和疼痛相关的淋巴疾病，以及 增强肌肉疼痛的交感神经激活。 该提案的具体目的是： 目标1：定义不同类型的机械敏感和代谢敏感的感觉神经元 根据骨骼肌肉对肌肉收缩的反应来支配骨骼肌肉。 目标2：确定肌肉收缩期间产生的化学介质是否负责 在肌肉过程中，机械敏感肌肉感觉神经元的一部分 收缩。 AIM 3：确定分泌感受器和元动物 - 无吸引者是否也对机械力做出反应 在肌肉收缩期间产生。 目标4：确定骨骼肌感觉神经元信号疼痛和 通过直接成像神经元末端进行疲劳。