Central role of JNK/Jun cascade in visceral nociception

JNK/Jun 级联在内脏伤害感受中的核心作用

• 批准号: 6867817
• 负责人: Li Fang
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867817
• 关键词: JUN kinase; behavior test; cell surface receptors; exploratory behavior; immunofluorescence technique; laboratory rat; neural information processing; neurogenetics; pain; receptor expression; regulatory gene; spinal cord; substance P; transcription factor; western blottings

DESCRIPTION (provided by applicant): Chronic visceral pain, especially pain from irritable bowel syndrome or visceral cancer pain, results in major social and health problems and represents one of the most common causes of work absenteeism, long term suffering and disability. Recently, midline myelotomy, a neurosurgical intervention which severs midline axons in the spinal dorsal column, has proved to be successful in alleviating otherwise visceral cancer pain. This approach is based on the interruption of a newly discovered pathway, the postsynaptic dorsal column (PSDC) pathway that transmits visceral painful information. However, the neurobiology of this pathway for visceral nociceptive transmission is inadequately understood. The major objective of this grant application is to examine the role of the immediate early gene, c-Jun, and its regulatory N-terminal protein kinase (JNK) and JNK subunits, in spinal PSDC neurons that process visceral nociceptive information. We hypothesize that the response of spinal viscero-sensitive neurons, especially PSDC neurons, involves the enhancement of c-Jun and phospho-c-Jun and that their activation is regulated by JNK phosphorylation. We will use multidisciplinary approaches, including morphological, molecular, electrophysiological and pharmacological approaches as well as behavioral tests to examine whether the JNK/c-Jun cascade is involved in central visceral nociception, especially in the PSDC pathway, in a rat model of experimentally induced visceral pain. To test our hypothesis, the specific aims of our studies are to measure during visceral pain stimulation: I) the activation of the transcription factor c-Jun and its phosphorylation in the rat spinal cord and specifically in the PSDC pathway; II) the changes in expression of p-c-Jun by inhibition of JNK/c-Jun cascade following visceral pain and determine if changes occur in cellular response of PSDC neurons, as well as in exploratory behavior; III) the expression of neurokinin NK1 receptors in spinal cord and PSDC neurons following inhibition of JNK activity. These studies are important because they should elucidate the signal-transduction mechanisms involved in the processing of visceral nociception that may, in turn, lead to development of drugs selective for management of visceral pain.

描述（由申请人提供）：慢性内脏疼痛，特别是肠易激综合征或内脏癌疼痛引起的疼痛，会导致重大的社会和健康问题，是导致缺勤、长期痛苦和残疾的最常见原因之一。最近，中线髓切开术，一种切断脊背中线轴突的神经外科干预，已被证明在减轻内脏癌性疼痛方面是成功的。这种方法是基于一个新发现的通路，即传递内脏疼痛信息的突触后背柱（PSDC）通路的中断。然而，这种内脏伤害性传递途径的神经生物学尚不充分了解。该资助申请的主要目的是研究即时早期基因c-Jun及其调控n端蛋白激酶（JNK）和JNK亚基在处理内脏伤害性信息的脊髓PSDC神经元中的作用。我们假设脊髓脏器敏感神经元，特别是PSDC神经元的反应涉及c-Jun和phospho-c-Jun的增强，并且它们的激活受JNK磷酸化的调节。我们将采用多学科方法，包括形态学、分子、电生理和药理学方法以及行为测试来检验JNK/c-Jun级联是否参与中枢内脏伤害感受，特别是PSDC通路，在实验诱导的内脏疼痛大鼠模型中。为了验证我们的假设，我们研究的具体目的是测量内脏疼痛刺激期间：1)大鼠脊髓中转录因子c-Jun的激活及其磷酸化，特别是在PSDC通路中；II)通过抑制JNK/c-Jun级联对内脏疼痛后p-c-Jun表达的变化，判断PSDC神经元的细胞反应是否发生变化，以及探索行为是否发生变化；III)抑制JNK活性后脊髓和PSDC神经元中神经激肽NK1受体的表达。这些研究很重要，因为它们应该阐明内脏痛觉加工过程中涉及的信号转导机制，进而可能导致选择性治疗内脏疼痛的药物的开发。