Cell Cycle Pathway Inhibition Decreases Peripheral Neuropathic Pain

描述(申请人提供)：神经性疼痛影响超过3%的美国人口。它被描述为严重、持久和对常规治疗高度耐药。因此，神经性疼痛会导致这些患者终身痛苦和生活质量下降。神经病理性疼痛的发生和持续的机制尚不清楚，但有几个因素可能有助于其发展，包括脊髓背角(SDH)的星形胶质细胞和小胶质细胞的激活以及背根神经节(DRG)的卫星胶质细胞的激活。所有这些因素都可以增加DRG和SDH神经元的超兴奋性，从而增加疼痛的传递。中枢神经系统损伤后，细胞周期通路被激活，导致星形胶质细胞增殖和小胶质细胞活化并伴有炎症。这种对细胞周期激活的反应可能有助于中枢神经病理性疼痛的发展。本研究的目的是研究细胞周期在周围神经病理性疼痛中的作用，并验证我们的假设，即抑制细胞周期通路可以减少周围神经损伤后神经元的过度兴奋性和机械性痛觉异常，可能是通过减少脊髓星形胶质细胞增生和背根节卫星神经胶质细胞的激活。在周围神经损伤(部分坐骨神经结扎)的小鼠模型中，使用积极的行为测试、电生理记录、Western印迹和免疫组织化学分析，我们将用以下方法验证我们的假设 以下是具体目标。具体目的1：证实在小鼠周围神经损伤模型中，脊髓背角(SDH)和背根节(DRG)细胞周期通路被激活。特异性目的2：证明抑制TH、SDH和DRG的细胞周期激活可减轻周围神经损伤后的痛觉异常和神经元的过度兴奋性。这项研究的结果将是非常重要的，并可以迅速从临床前到 临床环境，因为几种细胞周期抑制药物已经在癌症治疗的临床试验中。这项研究的发现也将产生广泛的影响，并增加我们在慢性疼痛状态下的机制知识。

DESCRIPTION (provided by applicant): Neuropathic pain affects over 3% of the U.S. population. It is described as being severe, persistent and highly resistant to conventional treatment. As such, neuropathic pain results in life-long suffering and decreased quality of life for these patients. The mechanisms underlying the development and persistence of neuropathic pain remain unclear; however, there are several factors that could contribute to its development, including astroglial and microglial activation in the spinal dorsal horn (SDH) and activation of satellite glial cells in the dorsal root ganglia (DRG). All of these factors can contribute to increased hyperexcitability of DRG and SDH neurons, which increases pain transmission. Following nerve injury in the central nervous system, cell cycle pathways are activated that lead to astroglial proliferation and microglial activation with inflammation. This response to cell cycl activation may contribute to the development of central neuropathic pain. The purpose of this study is to examine the role of the cell cycle in peripheral neuropathic pain and test our hypothesis that inhibiting the cell cycle pathway decreases neuronal hyperexcitability and mechanical allodynia after peripheral nerve injury, likely by reducing astrogliosis in the spinal cord and satellite glial cell activation in the DRG. Using nocifensive behavioral testing, electrophysiological recording, Western blot and immunohistochemical analyses in a mouse model of peripheral nerve injury (partial sciatic nerve ligation), we will test our hypothesis with the following Specific Aims. Specific Aim 1: To demonstrate that the cell cycle pathway is activated in the spinal dorsal horn (SDH) and dorsal root ganglia (DRG) in a mouse model of peripheral nerve injury. Specific Aim 2: To demonstrate that inhibiting cell cycle activation in th SDH and DRG decreases allodynia and neuronal hyperexcitability after peripheral nerve injury. The results of this study will be highly important and quickly translatable from the preclinical to the clinical setting, since several cell cycle inhibitor drugs are already in clinical trials for cncer treatment. The findings from this study will also have a broad impact and increase our mechanistic knowledge across chronic pain states.