Immediate and Delayed Effects of Morphine on Brain Circuits: Animal and Human Cor

描述（由申请人提供）：研究。即使在没有疼痛的情况下，危重新生儿和儿童也会接受长时间的阿片类药物镇静，以减少焦虑、躁动、应激反应，并促进通气。这种治疗与阿片类药物耐受性和依赖性的高发以及长期神经发育迟缓、神经认知和运动障碍有关。这表明，产后早期阿片类药物治疗有显著改变神经通路的风险。研究表明，成年患者长期接触阿片类药物后，杏仁核体积和连通性显著减少。杏仁核是一种复杂的结构，参与多种系统的调节，包括疼痛和成瘾。然而，阿片类药物对发育中的大脑杏仁核的影响及其可能的长期负面影响尚不清楚。我们假设，与直到青春期或成年期才接触吗啡的受试者相比，新生儿期长期接触吗啡会导致杏仁核和相关结构在以后的生活中体积和连通性显著下降。这一发现可能意味着对吗啡成瘾的敏感性。这项研究的独特之处在于，它利用神经影像学、行为和免疫组织化学技术（AIM 1），以及神经影像学技术（AIM 2），对不同年龄的大鼠和儿童长期暴露于吗啡的影响进行了研究。在大鼠和儿童的功能磁共振成像（fMRI）将允许长期吗啡给药及其长期影响的翻译系统水平的调查。作为AIM 1的一部分，阿片诱导的杏仁核神经可塑性将通过神经化学标记物和行为测试进行机制检查，以确定吗啡效应中神经胶质作用的个体发生。最终，通过定义动物模型和人类相关性，这项工作将使这一重大临床问题的转化方法成为可能。它将代表未来广泛长期的基础

DESCRIPTION (provided by applicant): 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.