Role of ASIC3 in the etiology of fibromyalgia

描述(申请人提供)：大约10%-15%的美国人口患有慢性广泛性疼痛(CWP)；而20%-25%的人口患有慢性区域性肌肉疼痛。肌肉骨骼疼痛的病因和发病机制尚不清楚。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中获得的。此外，肌肉疼痛的外周起始者几乎是未知的，但很可能是肌肉损伤后慢性疼痛发展的关键。最近，我们发现，在酸敏感离子通道ASICS零突变的小鼠中，肌肉刺激引起的机械性痛敏不会发生。然而，从这些实验中还不清楚ASICS在支配DRG的肌肉(发生伤害的地方)或皮肤(发生测试的地方)中的缺失是否对机械性痛敏的发展至关重要，以及ASICS是否同时参与肌肉诱导的痛敏的早期急性阶段和后期维持阶段。由于皮肤疼痛模型在没有ASICS的小鼠中不受影响，数据还表明ASICS在支配肌肉的感觉背根神经节(DRG)神经元中的表达相对于皮肤是独特的。因此，这些目标将检验以下假设：1)肌肉中的ASIC3是肌肉损伤所致的皮肤机械性痛敏全面发展的关键因素；2)肌肉和/或DRG神经元中ASIC3的mRNA和蛋白表达，以及支配DRG的肌肉中ASIC电流在肌肉损伤后以时间依赖的方式增加。这些特异性的目的是确定ASICS在基因敲除小鼠中的位置特异性(肌肉与皮肤)表达，在野生型小鼠中ASICS的下调，或在肌肉中对ASICs的药物阻断是否介导了肌肉损伤引起的机械性痛觉过敏。他们还将确定将在肌肉损伤后的两周内在选定的时间确定ASICS的表达--mRNA、蛋白质和功能。作为比较，我们将同时分析TRPV1。预计肌肉中的ASICS，而不是皮肤中的ASICS，将在继发性皮肤机械性痛敏的发展中起重要作用。我们进一步期望支配肌肉的DRG神经元中ASICS表达的变化将与肌肉损伤后机械性痛敏的发展和持续时间相关。了解启动慢性肌肉疼痛发展的介质和分子对于开发旨在治疗肌肉骨骼疼痛的新的治疗策略至关重要。这些研究可能导致以外周为基础的治疗方法来控制疼痛，而不会产生不良的中枢神经系统副作用，包括基因治疗。

DESCRIPTION (provided by applicant): Approximately 10-15% of the U.S. 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 not well understood. Most 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. Nevertheless, 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 and 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.