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

肌肉疼痛和疲劳几乎影响着所有人一生中的某个阶段。目前，有效的治疗方法 短期肌肉疼痛显然是不够的，而对慢性肌肉疼痛进行适当的治疗更是糟糕。 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。我们的 长期目标是确定肌肉剧烈疼痛、疼痛和疲劳的基本机制。 到感觉和运动系统。我们之前已经用小鼠模型中的发现来证明 质子、乳酸和三磷酸腺苷的结合是激活肌肉感觉神经元的必要条件和充分条件。在……里面 我们在人类受试者中进行的翻译研究表明，这三种代谢物的组合激活了 受试者的肌肉酸痛和疲劳感。我们建议在这里使用几只转基因小鼠 这将使第一次有可能确定分子、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 也将使我们有可能确定许多不同类型的传入信号选择性地 自主神经功能的许多不同方面，使我们能够在广泛的肌肉血液流动中发挥作用。 最后，这些老鼠将使我们不仅可以直接成像肌肉的细胞体 支配神经元，但直接观察两者对骨骼肌神经末梢的激活 代谢物和机械刺激。这些图像可以让我们确定触发的机制 穴位“、肌肉酸痛的搏动性、与肌肉疲劳和疼痛有关的淋巴疾病以及 交感神经激活增强的肌肉疼痛。 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 根据骨骼肌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对 肌肉过程中机械敏感型肌肉感觉神经元亚群的增强 收缩。 目标3：确定代谢物受体和代谢物伤害性感受器是否也对机械力做出反应 在肌肉收缩时产生。 目的4：确定骨骼肌感觉神经元的位置和结构，以传递疼痛和 通过直接对神经末梢进行成像而产生的疲劳。

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.