Central role of JNK/Jun cascade in visceral nociception

描述（由申请人提供）：慢性内脏痛，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，中线脊髓切开术，切断脊髓背柱中线轴突的神经外科干预，已被证明是成功的，以减轻内脏癌性疼痛。这种方法是基于一个新发现的通路，传递内脏疼痛信息的突触后背柱（PSDC）通路的中断。然而，这一途径的内脏伤害性传递的神经生物学是不充分的理解。这项资助申请的主要目的是研究即时早期基因c-Jun及其调节性N-末端蛋白激酶（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。我们假设脊髓内脏敏感神经元，特别是PSDC神经元的反应，涉及c-Jun和磷酸化c-Jun的增强，并且它们的激活受JNK磷酸化调节。我们将使用多学科的方法，包括形态学，分子，电生理和药理学的方法以及行为测试，以检查是否JNK/c-Jun级联参与中枢内脏伤害性感受，特别是在PSDC通路，在大鼠模型的实验诱导内脏痛。为了验证我们的假设，我们研究的具体目的是测量内脏痛刺激期间：I）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）内脏痛后通过抑制JNK/c-Jun级联反应而引起的p-c-Jun表达的变化，并确定PSDC神经元的细胞反应是否发生变化，以及探索行为; III）抑制JNK活性后脊髓和PSDC神经元中神经激肽NK 1受体的表达。这些研究是重要的，因为它们应该阐明参与内脏伤害性感受处理的信号转导机制，这可能反过来导致开发选择性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.