The role of ERK in affective pain

ERK 在情感性疼痛中的作用

• 批准号: 7002712
• 负责人: RU-RONG JI
• 金额: $ 3.12万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002712
• 关键词: NMDA receptors; afferent nerve; behavioral /social science research tag; brain derived neurotrophic factor; cAMP response element binding protein; cingulate gyrus; disease /disorder model; dorsal horn; emotions; enzyme activity; gene expression; glutamates; immunocytochemistry; in situ hybridization; inflammation; laboratory rat; long term memory; mitogen activated protein kinase; nerve injury; pain; phosphorylation; spinal ganglion; substance P; transcription factor; western blottings

DESCRIPTION (provided by applicant) Painful stimuli evoke pain sensation as well as unpleasant emotional feelings, and the emotional responses should be considered as an essential part of the pain experience. Clinical observations indicate that the debilitating nature of persistent pain induced by tissue injury (inflammatory pain) and nerve injury (neuropathic pain) is related to the suffering or anxiety the pain induces. Both persistent pain induced hypersensitivity (including hyperalgesia: increased responsiveness to noxious stimuli, and allodynia: painful responses to innocuous stimuli) and accompanied negative emotion (such as anxiety, angry, worry, fear, aversion, and related memory) can be regulated by transcriptional, translational, and post-translational mechanisms. The MAP kinase family member ERK (extracellular signal-regulated kinase) plays an important role in intracellular signaling and is implicated in pain hypersensitivity via these regulatory mechanisms. In the parent grant (RO1 NS40698), we focus on the role of ERK activation in primary sensory and dorsal horn neurons associated with peripheral and central sensitization, inflammatory pain, and gene transcription. To extend our previous study, the aim of this Fogarty proposal is to assess the involvement of the ERK in persistent pain-induced negative emotion in the anterior cingulate cortex (ACC). The project will test the following hypotheses: 1) ERK is activated in the ACC neurons following pain-related emotional affect and persistent pain-induced hypersensitivity, 2) ERK activation leads to CREB phosphorylation and the expression of CRE-containing genes in the ACC, 3) ERK activation in the ACC contributes to the induction and maintenance of affective pain. A number of different approaches, including immunostaining, western blot, and in situ hybridization will be used to detect protein and mRNA expression. A formalin-induced conditioned place avoidance (F-CPA) animal model will be used to discriminate sensory and affective component of pain. These results should provide further insights into the role of an intracellular signal cascade in the generation of sensation and negative emotion of persistent pain.

描述(由申请人提供) 疼痛刺激会引起痛感和不愉快的情绪，而情绪反应应该被认为是疼痛体验的重要组成部分。临床观察表明，组织损伤(炎症性疼痛)和神经损伤(神经病理性疼痛)引起的持续性疼痛的衰弱性质与疼痛引起的痛苦或焦虑有关。持续疼痛引起的超敏反应(包括痛觉过敏：对伤害性刺激的反应增强，以及超敏：对无害刺激的痛苦反应)和伴随的负面情绪(如焦虑、愤怒、担忧、恐惧、厌恶和相关记忆)都可以通过转录、翻译和翻译后机制进行调节。MAP激酶家族成员ERK(细胞外信号调节激酶)在细胞内信号转导中发挥重要作用，并通过这些调节机制参与疼痛超敏反应。在母基金(RO1NS40698)中，我们重点研究ERK激活在初级感觉神经元和背角神经元中的作用，这些神经元与外周和中枢敏化、炎性疼痛和基因转录有关。为了扩展我们之前的研究，这项Fogarty建议的目的是评估ERK在持续性疼痛诱导的前扣带皮质(ACC)负性情绪中的参与。本项目将验证以下假设：1)在与疼痛相关的情绪影响和持续的疼痛诱导的超敏反应之后，ERK在ACC神经元中被激活；2)ERK激活导致CREB磷酸化，并在ACC中表达含CRE的基因；3)在ACC中ERK的激活有助于情感性疼痛的诱导和维持。许多不同的方法，包括免疫染色，蛋白质印迹和原位杂交将被用来检测蛋白质和mRNA的表达。福尔马林诱导的条件性位置回避(F-CPA)动物模型将被用来区分疼痛的感觉和情感成分。这些结果应该为进一步深入了解细胞内信号级联在持续性疼痛的感觉和负面情绪产生中的作用提供了进一步的见解。