Central role of JNK/Jun cascade in visceral nociception

描述(申请人提供)：慢性内脏疼痛，特别是肠易激综合征引起的疼痛或内脏癌症疼痛，会导致重大的社会和健康问题，是导致旷工、长期痛苦和残疾的最常见原因之一。最近，中线脊髓切开术，一种切断脊髓背柱中线轴突的神经外科手术，被证明在缓解其他内脏癌症疼痛方面取得了成功。这种方法的基础是阻断一条新发现的通路，即传递内脏疼痛信息的突触后背柱通路。然而，这条内脏伤害性信息传递途径的神经生物学还不够清楚。这项拨款申请的主要目的是研究即刻早期基因c-jun及其调控的N末端蛋白激酶(JNK)和JNK亚单位在处理内脏伤害性信息的脊髓PSDC神经元中的作用。我们假设脊髓内脏敏感神经元，尤其是PSDC神经元的反应涉及c-jun和磷酸化c-jun的增强，它们的激活受JNK磷酸化的调节。我们将使用多学科的方法，包括形态、分子、电生理和药理学方法以及行为测试来检验JNK/c-jun级联通路是否参与实验性内脏痛大鼠模型的中枢内脏伤害性感受，特别是PSDC通路。为了验证我们的假设，我们研究的具体目标是在内脏痛刺激过程中：i)转录因子c-jun的激活及其在大鼠脊髓中的磷酸化，尤其是在PSDC通路中；ii)通过抑制JNK/c-jun级联反应来改变p-c-jun的表达，以确定是否会发生PSDC神经元的细胞反应及探索行为的变化；iii)NK1受体在抑制JNK活性后在脊髓和PSDC神经元中的表达。这些研究很重要，因为它们应该阐明内脏伤害性感觉处理过程中涉及的信号转导机制，这反过来可能导致选择性地开发治疗内脏疼痛的药物。

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.