Cell Cycle Pathway Inhibition Decreases Peripheral Neuropathic Pain

细胞周期途径抑制可减轻周围神经性疼痛

• 批准号: 8425502
• 负责人: CYNTHIA L RENN
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-10 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425502
• 关键词: Address; Affect; Astrocytes; Attenuated; Behavioral; Brain; Cell Cycle; Cell Cycle Inhibition; Cell Cycle Proteins; Cells; Clinical; Clinical Trials; Complication; Cyclin-Dependent Kinase 5; Data; Development; Electrophysiology (science); Etiology; Evaluation; Family; Goals; Harvest; Healthcare; Hyperalgesia; In Vitro; Inflammation; Injection of therapeutic agent; Knowledge; Lead; Life; Ligation; Link; Malignant Neoplasms; Mission; Modeling; Mus; Nerve; Neuraxis; Neuroglia; Neurons; Nociception; Pain; Pain management; Pathway interactions; Patient Care; Patients; Peripheral; Peripheral Nerves; Peripheral nerve injury; Pharmaceutical Preparations; Phosphorylation; Play; Population; Posterior Horn Cells; Process; Proteins; Quality of life; Reporting; Resistance; Role; Signal Transduction; Societies; Spinal; Spinal Cord; Spinal Ganglia; Strategic Planning; Symptoms; Tactile; Testing; Tissues; United States National Institutes of Health; Western Blotting; allodynia; astrogliosis; behavior test; chronic pain; cohort; conventional therapy; dorsal horn; effective therapy; extracellular; flavopiridol; improved; in vivo; inhibitor/antagonist; insight; intraperitoneal; mechanical allodynia; mouse model; nerve injury; neuroinflammation; neuronal cell body; neuroprotection; new therapeutic target; painful neuropathy; pre-clinical; prevent; protein expression; public health relevance; response; roscovitine; sciatic nerve; spontaneous pain; transmission process

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.

描述（由申请人提供）：神经性疼痛影响美国3％以上的人群。它被描述为严重，持久和高度抵抗常规治疗。因此，神经性疼痛会导致这些患者的终身痛苦和生活质量降低。神经性疼痛发育和持久性的基础机制尚不清楚。但是，有几个因素可能有助于其发展，包括脊柱背角（SDH）中的星形胶质细胞和小胶质细胞激活以及背侧根神经节（DRG）中卫星神经胶质细胞的激活。所有这些因素都可能导致DRG和SDH神经元的过度兴奋性增加，从而增加疼痛的传播。在中枢神经系统中神经损伤后，激活细胞周期途径，从而导致星形胶质细胞增殖和随着炎症的小胶质细胞激活。这种对细胞Cycl激活的反应可能有助于中枢神经性疼痛的发展。这项研究的目的是检查细胞周期在周围神经性疼痛中的作用，并检验我们的假设，即抑制细胞周期途径可降低外周神经损伤后神经元的过度兴奋性和机械性异常性疾病，这可能是通过脊髓胶质细胞和卫星胶质细胞活化DRG的降低星形胶质症的可能性。在外围神经损伤的小鼠模型（部分坐骨神经结扎）中，使用单一性行为测试，电生理记录，蛋白质印迹和免疫组织化学分析，我们将通过使用 以下特定目标。具体目的1：证明细胞周期途径在脊柱背角（SDH）和背根神经节（DRG）中激活。具体目的2：证明抑制TH和DRG中细胞周期激活会降低周围神经损伤后的异肌和神经元过度兴奋性。这项研究的结果将非常重要，并且可以从临床前迅速转换为 临床环境，因为几种细胞周期抑制剂药物已经进行了CNCER治疗的临床试验。这项研究的发现还将产生广泛的影响，并增加我们在慢性疼痛状态的机械知识。