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、激动、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生率以及长期神经发育迟缓、神经认知和运动障碍有关。这表明，出生后早期阿片类药物治疗存在神经通路显著改变的风险。研究表明，成年患者长期暴露于阿片类药物后，杏仁核体积和连通性显著降低，且与剂量相关。杏仁核是一个复杂的结构，已知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，在新生儿期延长吗啡暴露将导致显着减少的体积和连接的杏仁核和相关结构在以后的生活相比，受试者没有暴露于吗啡，直到青春期或成年。这些发现可能意味着对吗啡成瘾性的敏感性。这项建议是独特的，在其翻译的努力，以确定长期的吗啡暴露在不同年龄的大鼠使用神经影像学，行为和免疫组织化学技术（AIM 1），以及在儿童使用神经影像学（AIM 2）的影响。功能性磁共振成像（fMRI）在大鼠和儿童将允许翻译系统水平的调查长期吗啡给药及其长期影响。作为AIM 1的一部分，将使用神经化学标记物和行为测试来机械地检查杏仁核中阿片样物质诱导的神经可塑性，以确定神经胶质细胞在吗啡效应中的作用的个体发生。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。它将代表未来广泛的长期基础， 研究目的：寻找一种新的年龄特异性连续治疗方法，以减少早期长期使用吗啡的长期后遗症。候选人我于1994年在塞尔维亚贝尔格莱德医学院获得医学博士学位，并于2000年在芝加哥伊利诺伊大学获得药理学博士学位。我在同一机构进行博士后培训（2000-2003年），耶鲁大学耶鲁纽黑文医院麻醉住院医师（2004-2007年）和哈佛医学院波士顿儿童医院儿科麻醉研究员（2008年），我目前在那里担任儿科麻醉师。我在2008年获得了麻醉学认证。这次培训使我在基础科学和以病人为导向的临床工作方面建立了强大的背景。对于我的独立职业，我想把两者结合起来。我特别感兴趣的是解决与儿童长期阿片类药物给药引起的临床挑战有关的问题，特别是关于中枢适应长期吗啡暴露的年龄依赖性和长期后遗症。这是一个与儿科和麻醉的日常临床实践密切相关的及时话题。背景下 K 08奖，拟议的研究提供了机会，获得专业知识，在相关方面的功能磁共振成像在啮齿动物模型，以及在不同年龄的儿童。获得K 08奖将大大促进我的学术生涯，让我实现我的短期培训目标：扩大我的专业知识与动物和人类神经成像使用功能磁共振成像培训的新领域，并开发成功的R 01资助申请的技能。我的长期目标是作为一名临床医生/科学家获得学术独立，并建立自己的研究团队。环境在拟定的K 08项目期间，我将收到大卫·博尔苏克（导师）、利诺·贝塞拉（共同导师）、P·埃伦·格兰特（顾问）、罗伯特·C·Tasker（Advisor）和Kathryn G. Commons（顾问），使我的研究经验多样化，并获得新的技能和观点。这种导师和顾问的合作是理想的，以帮助我达到独立作为一个调查员与必要的国家的最先进的培训。拟定研究将在波士顿儿童医院、马萨诸塞州总医院和哈佛医学院的实验室和设施中进行。这些实验室中的每个实验室在与拟议研究的假设和具体目标相关的科学调查方面都拥有良好的记录。

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.