Role of ASIC3 in the etiology of fibromyalgia

描述（由申请人提供）：大约10-15%的美国人口患有慢性广泛性疼痛（CWP）;而20-25%的人口患有慢性局部肌肉疼痛。疼痛性肌肉骨骼疾病的病因和发病机制还不清楚。大多数关于疼痛机制的知识都是从使用皮肤疼痛模型的研究中获得的。此外，肌肉疼痛的外周引发者实际上是未知的，但可能是肌肉损伤后慢性疼痛发展的关键。最近，我们发现肌肉损伤诱导的机械性痛觉过敏在酸敏感离子通道ASICS无效突变的小鼠中不会发生。然而，从这些实验中尚不清楚是否在DRG神经支配肌肉（其中发生损伤）或皮肤（其中发生测试）中ASICS的缺乏对于机械性痛觉过敏的发展是关键的，以及ASICS是否涉及肌肉诱导的痛觉过敏的早期急性期和后期维持期。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，这些目的将检验以下假设：1）肌肉中的ASIC 3是肌肉损伤诱导的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，以及肌肉损伤后DRG神经支配肌肉中的ASIC电流以时间依赖性方式增加。特定目的旨在确定基因敲除小鼠中ASICS的位点特异性（肌肉与皮肤）表达、野生型小鼠中ASICS的下调或肌肉中ASICS的药理学阻断是否介导肌肉损伤诱导的机械性痛觉过敏。他们还将确定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。预期肌肉中的ASICS而非皮肤中的ASICS对于继发性皮肤机械性痛觉过敏的发展将是重要的。我们进一步预期，ASICS在支配肌肉的DRG神经元中表达的变化将与肌肉损伤后机械性痛觉过敏的发展和持续时间相关。了解介体和分子，启动发展的慢性肌肉疼痛是至关重要的发展新的治疗策略，旨在治疗肌肉骨骼疼痛。这些研究可能会导致基于外周的治疗方法来控制疼痛，而不会产生不良的CMS（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.