Role of ASIC3 in the etiology of fibromyalgia

大约10-15%的美国人口患有慢性广泛性疼痛（CWP）;而20-25%的美国人口患有慢性广泛性疼痛（CWP）。 慢性局部肌肉疼痛。肌肉骨骼疼痛的病因和发病机制 条件知之甚少。我们关于疼痛机制的大部分知识都是从 使用皮肤疼痛模型的研究。此外，肌肉疼痛的外周引发者几乎是未知的，但 可能是肌肉损伤后慢性疼痛发展的关键。最近，我们发现， 在酸敏感离子无效突变的小鼠中，肌肉损伤诱导的痛觉过敏不会发生 通道，ASICS。然而，从这些实验中尚不清楚是否在DRG中缺乏ASICS 神经支配肌肉（发生损伤的地方）或皮肤（发生测试的地方）对于 机械性痛觉过敏，如果ASICS涉及早期急性期以及后期 肌肉诱发痛觉过敏的维持期。由于小鼠皮肤疼痛模型不受影响， 没有ASICS，数据还表明ASICS在感觉背根神经节（DRG）中的表达 支配肌肉的神经元相对于皮肤是独特的。因此，这些目标将检验假设， 1)肌肉中的ASIC 3是皮肤机械性痛觉过敏充分发展的关键因素 2）肌肉和/或DRG神经元中的ASIC 3 mRNA、蛋白表达，和 肌肉损伤后，支配肌肉的DRG中的ASIC电流以时间依赖性的方式增加。 具体目的旨在确定ASICS在小鼠中的位点特异性（肌肉vs.皮肤）表达是否与ASICS的表达相关。 基因敲除小鼠、野生型小鼠中ASICS的下调或肌肉中ASICs的药理学阻断 介导由肌肉损伤引起的机械性痛觉过敏。他们也将决定 ASICS表达- mRNA，蛋白质和功能-在肌肉损伤后两周的选定时间。我们 将同时分析TRPV 1作为比较。预计肌肉中的ASICS，而不是皮肤中的ASICS， 对继发性皮肤机械性痛觉过敏的发展很重要。我们还期望， ASICS在支配肌肉的DRG神经元中表达的变化可能与脊髓损伤的发生发展有关。 和肌肉损伤后机械性痛觉过敏的持续时间。了解介质和分子 启动慢性肌肉疼痛发展对于开发新的治疗策略是至关重要的， 治疗肌肉骨骼疼痛这些研究可能会导致基于外周的治疗方法， 控制疼痛，没有不良的CMS（中枢神经系统）副作用，包括基因治疗。

Approximately 10-15% of the US population has chronic widespread pain (CWP); while 20-25% of the population has chronic regional muscle pain. The etiology and pathogenesis of painful musculoskeletal conditions are poorly understood. Most of our knowledge about mechanisms of pain has been obtained from studies using cutaneous pain models. Further, peripheral initiators of muscle pain are virtually unknown, but likely key to the development of chronic pain after muscle insult. Recently, we showed that mechanical hyperalgesia induced by muscle insult do not develop in mice with a null mutation of the acid-sensing ion channel, ASICS. However, it is not clear from these experiments whether the absence of ASICS in the DRG innervating muscle (where insult occurs) or in the skin (where testing occurs) is critical for development of mechanical hyperalgesia, and if ASICS is involved in both the early acute phase as well as the later maintenance phase of muscle-induced hyperalgesia. Since models of cutaneous pain are unaffected in mice without ASICS, the data also suggest that expression of ASICS in sensory dorsal root ganglion (DRG) neurons innervating muscle is unique relative to skin. Therefore, these aims will test the hypotheses that 1) ASIC3 in the muscle is a key factor for full development of cutaneous mechanical hyperalgesia induced by muscle insult, 2) ASIC3 mRNA, protein expression in muscle and/or DRG neurons, and ASIC currents in DRG innervating muscle increases in a time-dependent manner after muscle insult. The specific aims are designed to determine if site specific (muscle vs. skin) expression of ASICS in knockout mice, downregulation of ASICS in wild-type mice, or pharmacological blockade of ASICs in muscle mediates the mechanical hyperalgesia induced by muscle insult. They will also determine will determine ASICS expression - mRNA, protein, and function - at selected times for two weeks after muscle insult. We will analyze TRPV1 simultaneously as a comparison. It is expected that ASICS in muscle, but not skin, will be important for development of secondary cutaneous mechanical hyperalgesia. We further expect that changes in the expression of ASICS in DRG neurons innervating muscle will correlate with the development and duration of mechanical hyperalgesia after muscle insult. Understanding the mediators and molecules that initiate development of chronic muscle pain is critical to development of new treatment strategies aimed at treating musculoskeletal pain. These studies could lead to peripherally based therapeutic approaches to control pain without undesirable CMS (central nervous system) side effects, including gene therapy.