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%的美国人患有慢性广泛性疼痛 人们患有慢性区域性肌肉疼痛。肌肉骨骼疼痛的病因病机 人们对这些情况知之甚少。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，肌肉疼痛的外周始发者几乎是未知的，但 可能是肌肉损伤后慢性疼痛发展的关键。最近，我们展示了机械 酸感离子零突变小鼠不会出现肌肉刺激引起的痛觉过敏 频道，ASICS。然而，从这些实验中尚不清楚DRG中是否存在ASICS 支配肌肉(发生侮辱的地方)或皮肤(发生测试的地方)对于发展 机械性痛觉过敏，以及ASICS是否同时参与早期急性期和晚期 肌肉痛觉过敏的维持期。由于小鼠的皮肤疼痛模型不受影响 数据还表明，在没有ASICS的情况下，ASICS在感觉背根节(DRG)中的表达 支配肌肉的神经元与皮肤相比是独一无二的。因此，这些目标将检验以下假设 1)肌肉中的ASIC3是皮肤机械性痛觉过敏充分发展的关键因素 肌肉损伤诱导，2)肌肉和/或背根节神经元ASIC3mRNA和蛋白表达，以及 肌肉损伤后，支配背根神经节的ASIC电流呈时间依赖性增加。 这些特定的目的旨在确定ASICS的位置特异性(肌肉与皮肤)是否在 基因敲除小鼠，野生型小鼠ASICS下调，或药物对肌肉ASICs的阻断 调节肌肉损伤引起的机械性痛觉过敏。他们还将决定是否将决定 在肌肉损伤后的两周内，在选定的时间表达ASICS--mRNA、蛋白质和功能。我们 将同时分析TRPV1作为比较。预计肌肉中的ASICS，而不是皮肤中的ASICS，将 对继发性皮肤机械性痛敏的发生具有重要意义。我们还期待着 支配肌肉的背根节神经元ASICS表达的变化将与发育相关 肌肉损伤后机械性痛觉过敏的持续时间。了解介体和分子 启动慢性肌肉疼痛的发展对于制定新的治疗策略至关重要 在治疗肌肉骨骼疼痛方面。这些研究可能导致以外周为基础的治疗方法 控制疼痛而不产生不良的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.