GCAMP6 mice for determination of mechanisms of chronic muscle ache, pain and fatigue

 描述（由申请人提供）：GCAMP 6小鼠，用于确定慢性肌肉疼痛、疼痛和疲劳的机制。 肌肉疼痛和肌肉疲劳是许多慢性疾病的症状，包括纤维肌痛、慢性疲劳综合征、肌面疼痛、慢性紧张性头痛和颞下颌关节紊乱病。更多的患者生活质量下降，因为短期肌痛和疲劳，有时与治疗缓解，或由于未知的原因，成为慢性。我们的长期目标是确定强烈的肌肉疼痛，疼痛和疲劳的感觉和运动系统的信号的基本机制。我们以前在小鼠模型中使用的发现证明，质子，乳酸盐和ATP的组合是必要的，足以激活肌肉感觉神经元。在人类受试者的转化研究中，我们发现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。在这里，我们建议创建一个转基因小鼠，这将使之成为可能，第一次，图像的感觉神经元的活动，信号疼痛和疲劳的骨骼肌功能。这将使我们能够建立肌肉疼痛和肌肉疲劳的认知感觉的感觉信号通路的分子和细胞机制。它还可以直接观察肌肉疼痛中几种有争议现象的机制，包括触发点，肌肉疼痛和慢性偏头痛的脉动性质，与肌肉疲劳和肌肉疼痛相关的淋巴疾病，以及肌肉疼痛的交感神经激活增强。该提议的具体目标是：1）创建具有内源性钙传感器的小鼠，所述内源性钙传感器具有允许在支配感觉神经元的第III/IV组肌肉中表达的启动子。 2)使用这些小鼠记录III/IV传入反应低和高代谢物使用麻醉的体内制剂。这将允许与先前从被戏弄的肌肉神经纤维收集的手指肌肉记录和用钙成像记录的背根神经节神经元进行比较。 用这种方法，我们还将确定生理学上鉴定的III/IV组受体末梢神经支配的位置和结构（所有类型的伤害感受器和运动感受器，例如，机械感受器和代谢感受器）。

 DESCRIPTION (provided by applicant): GCAMP6 mice for determination of mechanisms of chronic muscle ache, pain and fatigue. Muscle pain and muscle fatigue are symptoms in many chronic diseases including Fibromyalgia, Chronic Fatigue Syndrome, Myofacial Pain, Chronic Tension Headache, and Temporomandibular Disorder. Many more patients have degraded quality of life because of short term myalgia and fatigue that sometimes remits with treatment, or for unknown reasons, becomes chronic. 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. Here we propose to create a transgenic mouse that will make it possible, for the first time, to image the activity of sensory neurons that signal pain and fatigue in functioning skeletal muscle. This will allow us to establish the molecular and cellular mechanisms of the sensory signaling pathways for cognitive sensations of muscle pain and muscle fatigue. It will also make it possible to directly observe the mechanisms of several controversial phenomena in muscle pain including trigger points, the pulsating nature of muscle ache and chronic and migraine headache, lymphatic disease association with muscle fatigue and muscle pain, and sympathetic activation enhancement of muscle pain. The specific aims for this proposal are: 1) Create mice that have endogenous calcium sensors with promoters that allow expression in Group III/IV muscle innervating sensory neurons. 2) Use these mice to record III/IV afferents responses to low and high metabolites using anesthetized in vivo preparations. This will allow comparisons with the digit muscle recordings collected from teased muscle nerve fibers previously, and dorsal root ganglion neurons recorded with calcium imaging. With this method we will also determine the location and structures that physiologically identified Group III/IV receptor endings innervate (both nociceptors and ergoreceptors of all types e.g., mechanoreceptor and metaboreceptor).