Research. Even in the absence of pain, critically ill neonates and children receive prolonged opioids for sedation to reduce anxiety, agitation, stress responses, and to facilitate ventilation. Such treatment is associated with a high incidence of opioid tolerance and dependence, as well as long-term neurodevelopmental delay, neurocognitive and motor impairments. This suggests that early postnatal opioid treatment runs the risk of significant alterations in neural pathways. Studies have demonstrated significant dose-related decreases in the amygdala volume and connectivity after long-term opioid exposure in adult patients. The amygdala is a complex structure known to be involved in the modulation of multiple systems, including pain and addiction. However, the impact of opioids on the amygdala in the developing brain and its possible long-term negative effects are unknown. We hypothesize that prolonged morphine exposure in the neonatal period will lead to a significant decrease in volume and connectivity of the amygdala and related structures later in life when compared to subjects not exposed to morphine until adolescence or adulthood. Such findings would imply possible sensitization to the addictive qualities of morphine. This proposal is unique in its translational effort to define the impact of prolonged morphine exposure in the rats of different ages using neuroimaging, behavioral, and immunohistochemical techniques (AIM 1), as well as in children using neuroimaging (AIM 2). Functional magnetic resonance imaging (fMRI) in both rats and children will allow a translational systems level investigation of prolonged morphine administration and its long-term effects. As part of AIM 1, opioid-induced neuroplasticity in the amygdala will be examined mechanistically using neurochemical markers and behavioral testing to define ontogeny of the glial role in morphine effects. Ultimately, by defining an animal model and a human correlate, this work will enable a translational approach of this significant clinical problem. It will represent the foundation for a future broad long-term research objective: search for a novel age-specific adjunctive therapy to minimize long-term sequelae of early administration of prolonged morphine. Candidate. I received my MD at the Medical School of Belgrade, Serbia in 1994, and my PhD in Pharmacology at the University of Illinois at Chicago in 2000. I conducted my postdoctoral training at the same institution (2000-2003), Anesthesia Residency at Yale New Haven Hospital, Yale University (2004-2007), and Pediatric Anesthesia Fellowship at Children's Hospital Boston, Harvard Medical School (2008), where I currently work as a Pediatric Anesthesiologist. I am board certified in Anesthesiology as of 2008. This training has allowed me to establish a strong background both in basic science and patient oriented clinical work. For my independent career, I would like to bring the two together. I am especially interested in addressing questions related to clinical challenges stemming from chronic opioid administration in children, particularly regarding age-dependent and long-term sequelae of central adaptations to prolonged morphine exposure. This is a timely topic of great relevance to daily clinical practice of Pediatrics and Anesthesia. In the context of the K08 award, the proposed research provides the opportunity to acquire expertise in relevant aspects of fMRI in a rodent model, as well as in children of different ages. To receive a K08 Award would substantially advance my academic career by allowing me to achieve my short-term training goals: expanding my expertise with a new domain of training in animal and human neuroimaging using fMRI, and developing skills for a successful R01 grant application. My long-term goal is to obtain academic independence as a clinician/scientist and to establish my own research team. Environment. During the proposed K08 program, I will have formal input from Drs. David Borsook (Mentor), Lino Becerra (Co-Mentor), P. Ellen Grant (Advisor), Robert C. Tasker (Advisor), and Kathryn G. Commons (Advisor), to diversify my research experience and to gain new skills and perspectives. This collaboration of mentors and advisors is ideal to help me reach independence as an investigator with the necessary state-of-the-art training. The proposed studies will be conducted in the laboratories and facilities of the Boston Children's Hospital, Massachusetts General Hospital, and Harvard Medical School. Each of these laboratories has a well-established track record in scientific investigation relevant to the hypothesis and specific aims of the proposed study.
Opioids, including morphine, remain a mainstream therapy for pain treatment and sedation of newborns. Unfortunately, prolonged administration of opioids leads to rapid development of analgesic tolerance and physical dependence at this early age. Using fMRI in children of all ages and in a developing rat model, this project will examine long-term effects of central adaptations to chronic morphine, including possible sensitization to the addictive qualities. Results will provide a foundation for future translational research for a nove adjunct therapy to improve age-specific pain treatment and attenuate long-term sequelae of prolonged opioid treatment.