Opioids, Stress and Noradrenergic Neurons

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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.