Opioids, Stress and Noradrenergic Neurons

描述(申请人提供)：本申请K02独立科学家奖是为了让我有更多的时间从事与研究相关的项目，并在鸦片和应激研究领域培养我的职业生涯。我最近从国家药物滥用研究所(NIDA)(R0I DA09082-05)获得了为期五年(2001-2006)的联邦拨款支持。题为“蓝斑-皮质通路的阿片类药物调制”的项目是最初由NIDA资助的HRST奖项目的继续。拟议的研究涉及与费城的另外两名研究人员合作，他们是费城儿童医院的教授丽塔·瓦伦蒂诺博士和宾夕法尼亚哈内曼医学院的研究助理教授米歇尔·佩奇博士。该项目的具体目标包括为影响蓝斑去甲肾上腺素能神经元的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的神经解剖学方法，确定CRF与阿片类药物相互作用对LC神经元活动影响的神经生理学方法，以及确定这些相互作用是否转化为皮质靶点的神经生理学方法。指导性假说是，压力使慢性肾功能衰竭和阿片类传入LC产生相反的影响。阿片类药物和CRF的影响之间的平衡可能维持了应对压力的主动和被动应对行为的平衡。LC对阿片类药物(阿片类药物耐受的结果)或CRF(先前应激的结果)敏感性的变化将改变这种平衡和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职员工在本提案的目标3中描述的合作已经开始，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，以检查暴露于鸦片类药物或游泳应激后LC神经元基因表达的差异。申请书中还描述了负责任的研究行为方面的适当培训。

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.