Morphine Actions on the Immune System

提交KO 2独立科学家奖的申请是为了使我能够投入更多的时间， 我的研究项目和其他与研究相关的活动，并进一步我在该领域的研究生涯 药物滥用的神经免疫学我研究的主要目标是确定滥用药物的影响， 例如吗啡对免疫反应及其进展的影响。我们以前曾报道过，慢性 暴露于吗啡通过脱敏抑制下丘脑-垂体-肾上腺（HPA）轴 白细胞介素-113（IL- 113）诱导下丘脑室旁核神经元激活， 脑参与HPA轴的激活，从而抑制IL-1 β 3诱导的促肾上腺皮质激素的转录 释放因子mRNA的下丘脑和减少生产的抗炎剂，如 肾上腺分泌的皮质酮相反，我们发现吗啡增强IL- 1[3]诱导的 免疫应答，如肠系膜小静脉中的白细胞-内皮粘附（莱亚）。因此，看来， 慢性吗啡暴露可通过破坏平衡而促进潜在的破坏性炎症反应 IL-1 β-介导的局部炎症反应，如莱亚，和IL-1 β-介导的抗炎作用之间的关系， HPA轴。最近，我的RO 1赠款（DA 07058-12）题为“吗啡对免疫系统的作用”，是 又延长了五年（3/15/02-1/31/07），我还获得了新的设备赠款 泽西岛高等教育委员会购买了一个序列检测系统，一个荧光成像仪，和一个 荧光板读数器。我的RO 1项目中的研究旨在扩展我们以前的发现，以定义 吗啡影响细菌感染进展的机制。具体目标是 定义细菌内毒素调节μ阿片受体（莫尔）的分子和细胞过程- 依赖性途径以及这种调节如何与内毒素休克的进展相关。KO 2奖项 这将使我能够投入最大的时间：1）我的研究项目的目标工作，2）获得 在使用最先进的方法，包括真实的时间PCR，荧光生物 检测和微阵列技术，3）指导研究生和初级研究人员，以及4）建立一个 正在进行的正式培训计划，在负责任的行为研究，我的实验室工作人员和学生。

This application for a KO2 Independent Scientist Award is submitted to enable me to devote additional time to my research projects and other research-related activities and to further my research career in the field of neuroimmunology of drug abuse. The primary goal of my research is to define the influence of drugs of abuse, such as morphine, on immune responses and their progression. We have previously reported that chronic exposure to morphine suppresses the hypothalamic-pituitary-adrenal (HPA) axis in vivo by desensitizing interleukin- 113(IL- 113)-induced neuronal activation of the hypothalamic paraventricular nucleus, an area of the brain involved in the activation of the HPA axis, thus, inhibiting IL-I f3-induced transcription of corticotropin releasing factor mRNA by the hypothalamus and decreasing the production of anti-inflammatory agents, such as corticosterone, by the adrenal gland. Conversely, we have found that morphine potentiates IL- 1[3-induced immune responses, such as leukocyte-endothelial adhesion (LEA), in mesenteric venules. Thus, it appears that chronic morphine exposure can promote a potentially damaging inflammatory reaction by disrupting the balance between IL-1 [3-mediated local inflammatory responses, such as LEA, and the anti-inflammatory effects of the HPA axis. Recently, my RO1 grant (DA 07058-12) entitled, "Morphine actions on the immune system", was renewed for an additional five years (3/15/02-1/31/07), and I was also awarded an equipment grant by the New Jersey Commission on Higher Education to purchase a sequence detection system, a fluorescent imager, and a fluorescent plate reader. The studies in my RO1 project are designed to extend our previous findings to define the mechanisms by which morphine influences the progression of bacterial infection. The Specific Aims are to define the molecular and cellular processes by which bacterial endotoxins modulate mu opioid receptor (MOR)- dependent pathways and how such modulation is related to the progression of endotoxin shock. This KO2 award will enable me to devote maximum time to: 1) working on the aims of my research projects, 2) gaining experience in the use of state-of-the-art methodologies, including real time PCR, fluorescence-based biological assays, and microarray technology, 3) mentoring research students and junior researchers, and 4) establishing an ongoing formal training program in the responsible conduct of research for my lab staff and students.