ERK/MAPK Activation and Pain Hypersensitivity

ERK/MAPK 激活和疼痛超敏反应

• 批准号: 6540359
• 负责人: RU-RONG JI
• 金额: $ 30.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-15 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540359
• 关键词: behavior test; biological signal transduction; brain derived neurotrophic factor; cAMP response element binding protein; dorsal horn; enzyme activity; genetic transcription; genetic translation; glutamates; growth factor; hyperalgesia; in situ hybridization; inflammation; laboratory rat; mitogen activated protein kinase; nerve injury; neurohormones; neurotransmitters; phosphorylation; spinal cord; spinal ganglion; substance P; western blottings

Clinical pain can be caused by tissue injury (inflammatory pain) and by nerve injury (neuropathic pain) and is typically characterized by hyperalgesia (increased responsiveness to noxious stimuli) and allodynia (painful responses to innocuous stimuli). Changes in the peripheral terminals of primary sensory neurons may lead to peripheral sensitization (an increased transduction sensitivity of nociceptors) whilst changes in the excitability of spinal dorsal horn neurons can result in central sensitization (an increased gain of sensory transmission), two major mechanisms contributing to pain hypersensitivity. Although short-term pain hypersensitivity is transcription-independent, persistent pain hypersensitivity may be the result of gene transcription- and protein synthesis-dependent mechanisms. The aim of this proposal is to assess the involvement of the MAPK (mitogen-activated protein kinase) family member ERK (extracellular signal-regulated protein kinase) in mediating both post-translational and transcriptional changes which contribute to inflammatory and neuropathic pain hypersensitivity. The project will examine ERK activation in primary sensory neurons in the dorsal root ganglia (DRG) and in dorsal horn neurons in vivo and in vitro and will test the hypotheses that 1) ERK activation contributes to peripheral and central sensitization, 2) ERK activation leads to CREB phosphorylation and the expression of CRE-containing genes in DRG and dorsal horn neurons, and 3) ERK activation contributes to the induction and maintenance of inflammatory pain and neuropathic pain. A number of different approaches, including immunostaining, western blot, and in situ hybridization to detect protein and mRNA expression, will be used, as well as behavioral tests. These results should provide insights into the role of intracellular signal transduction cascades in the pathogenesis of pain.

临床疼痛可能是由组织损伤（炎症性疼痛）和神经损伤（神经性疼痛）引起的，通常以痛觉过敏（对有害刺激的反应性增加）和异常性症（对无害刺激的疼痛反应）的特征。 原发性感觉神经元的外围末端的变化可能导致外周敏化（伤害感受器的转导灵敏度增加），而脊柱背侧角神经元的兴奋性的变化会导致中心敏感性（增加感觉传播的增加），有助于疼痛疼痛的两种主要机制。 尽管短期疼痛超敏反应是不依赖转录的，但持续性疼痛超敏反应可能是基因转录和蛋白质合成依赖机制的结果。 该提案的目的是评估MAPK（有丝分裂原激活的蛋白激酶）家族成员ERK（细胞外信号调节蛋白激酶）参与介导翻译后和转录变化，这有助于炎症性和神经性疼痛性高敏性。 The project will examine ERK activation in primary sensory neurons in the dorsal root ganglia (DRG) and in dorsal horn neurons in vivo and in vitro and will test the hypotheses that 1) ERK activation contributes to peripheral and central sensitization, 2) ERK activation leads to CREB ​​phosphorylation and the expression of CRE-containing genes in DRG and dorsal horn neurons, and 3) ERK激活有助于诱导和维持炎症性疼痛和神经性疼痛。 将使用许多不同的方法，包括免疫染色，蛋白质印迹和原位杂交以检测蛋白质和mRNA表达，以及行为测试。 这些结果应提供有关细胞内信号转导级联反应在疼痛发病机理中的作用的见解。