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

肌肉疼痛和疲劳影响几乎所有的人在他们的生活中的某个时候。目前，有效的治疗 短期肌肉疼痛显然是不充分的，而对慢性肌肉疼痛的充分治疗甚至更糟。 大量证据表明，III/IV组肌肉传入的外周感觉失调，以及 自主神经失调可能导致或促成短期和慢性肌肉疼痛和疲劳。 长期目标是确定强烈的肌肉疼痛，疼痛和疲劳信号的基本机制 到感觉和运动系统。我们以前在小鼠模型中的发现证明， 质子、乳酸盐和ATP的组合对于激活肌肉感觉神经元是必要的和足够的。在 在人类受试者中的转化研究表明，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个转基因小鼠 这将使人们有可能，第一次，以确定分子，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。这些小鼠 也将使我们有可能确定许多不同类型的传入，选择性地发出信号， 自主神经功能的许多不同方面，使我们能够在大范围的肌肉血流中发挥作用。 最后，这些老鼠将使我们不仅能够直接成像肌肉的细胞体 神经支配的神经元，但直接观察骨骼肌中的神经末梢的激活， 代谢物和机械刺激。这些图像可以让我们确定“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 交感神经激活增强肌肉疼痛。 这项建议的具体目标是： 目的1：定义不同类型的机械敏感和代谢敏感感觉神经元 基于它们对肌肉收缩的反应来支配骨骼肌。 目的2：确定肌肉收缩过程中产生的化学介质是否负责 在肌肉过程中，在机械敏感性肌肉感觉神经元的子集中观察到增强 收缩。 目的3：确定代谢感受器和代谢伤害感受器是否也对机械力作出反应 是肌肉收缩时产生的 目的4：确定骨骼肌痛觉神经元的位置和结构， 疲劳通过直接成像的神经元终端。

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.