Opioids, Stress and Noradrenergic Neurons

提交K 02独立科学家奖的申请是为了使我能够将更多的时间投入到与研究相关的项目中，并促进我在阿片类药物和压力研究领域的职业生涯。我最近收到了国家药物滥用研究所（NIDA）的联邦赠款支持（R 0 I DA 09082 -05），为期五年（2001-2006）。题为“蓝核-皮层通路的阿片类调节”的项目是最初由NIDA作为HRST奖资助的一个项目的继续。拟议的研究涉及与费城的另外两名研究人员的合作，他们是费城儿童医院的教授Rita Valentino博士和宾夕法尼亚州哈内曼医学院的研究助理教授Michelle Page博士。该项目的具体目标是整合神经解剖学方法，为阿片类药物和促肾上腺皮质激素释放因子（CRF）之间的相互作用提供细胞底物，影响蓝斑（LC）的去甲肾上腺素能神经元，神经生理学方法，以确定CRF-阿片类药物相互作用对LC神经元活动的影响，以及神经化学方法，以确定这些相互作用是否转化为皮质靶点。指导性假设是，压力使CRF和阿片类传入传入LC对该系统有相反的影响。阿片类药物和CRF之间的平衡可能维持应激反应中主动和被动应对行为的平衡。LC对阿片类药物（由于阿片类药物耐受）或CRF（由于先前的压力）敏感性的变化将改变这种平衡以及主动与被动应对行为的模式。这些合作努力将使我能够探索新的技术和实验方法。此外，与托马斯杰斐逊大学病理学、解剖学和细胞生物学系的教师合作（见本提案目标3），以促进我的职业发展。实验包括激光捕获显微切割与微阵列技术相结合，以研究暴露于阿片类药物或游泳应激后LC神经元中基因表达的差异。申请中还描述了在负责任地开展研究方面的适当培训。

DESCRIPTION (provided by applicant): This application for a K02 Independent Scientist Award is submitted to enable me to devote additional time to research-related projects and foster my career in the field of opiate and stress research. I have recently received federal grant support from the National Institute on Drug Abuse (NIDA) (R0 I DA09082-05) for five years (2001-2006). The project entitled "Opioid modulation of the coeruleo-cortical pathway" is a continuation of a project originally funded as an HRST Award by NIDA. The proposed studies involve collaborations with two other investigators in Philadelphia, Dr. Rita Valentino, a Professor at the Children's Hospital of Philadelphia and Dr. Michelle Page, a Research Assistant Professor at Hahnemann/Medical College of Pennsylvania. The Specific Aims of the project integrate neuroanatomical approaches to provide cellular substrates for interactions between opioids and corticotropin releasing factor (CRF) that impact on noradrenergic neurons of the locus coeruleus (LC), neurophysiological approaches to identify the impact of CRF-opioid interactions on LC neuronal activity and neurochernical approaches to determine whether these interactions are translated to cortical targets. The guiding hypothesis is that stress engages CRF and opioid afferents to the LC that have opposing influences on this system. The balance between opioid and CRF influences may maintain the balance of active and passive coping behaviors in response to stress. Changes in LC sensitivity to either opioids (as a result of opioid tolerance) or CRF (as a result of prior stress) would shift this balance and the pattern of active vs. passive coping behaviors. These collaborative efforts would enable me to explore new techniques and experimental approaches. Moreover, collaborations with faculty within the Department of Pathology, Anatomy and Cell Biology at Thomas Jefferson University described in Aim 3 of the present proposal have been initiated to enhance my career development. Experiments include laser capture microdissection combined with microarray technology to examine differences in gene expression in LC neurons following exposure to opiates or swim stress. Appropriate training in the responsible conduct of research is also described within the application.