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

描述(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期的阿片类药物镇静，以减少焦虑、激动、应激反应，并促进通风。这种治疗与阿片类药物耐受和依赖的高发生率以及长期的神经发育延迟、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有明显改变神经通路的风险。研究表明，成人患者长期使用阿片类药物后，杏仁核体积和连接性明显减少，这与剂量有关。杏仁核是一种复杂的结构，已知参与了包括疼痛和成瘾在内的多个系统的调节。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，与青春期或成年期之前不接触吗啡的受试者相比，新生儿期长期接触吗啡将导致杏仁核及相关结构的体积和连接性显著下降。这样的发现可能意味着对吗啡上瘾特性的敏感化。这项建议的独特之处在于，它的翻译工作是使用神经成像、行为和免疫组织化学技术(AIM 1)确定不同年龄段的大鼠长期吗啡暴露的影响，以及使用神经成像(AIM 2)确定儿童的影响。在大鼠和儿童身上进行的功能磁共振成像(FMRI)将允许对长期使用吗啡及其长期影响的翻译系统水平进行研究。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阿片类药物诱导的杏仁核神经可塑性，以确定神经胶质在吗啡效应中的个体发育作用。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翻译方法成为可能。它将代表着未来广泛而长期的基础 研究目的：寻找一种新的针对年龄的辅助疗法，以最大限度地减少长期使用吗啡的长期后遗症。候选人。1994年，我在塞尔维亚贝尔格莱德医学院获得医学博士学位，2000年在芝加哥伊利诺伊大学获得药理学博士学位。我在同一家机构接受博士后培训(2000-2003)，在耶鲁大学耶鲁纽黑文医院(Yale University New Haven)担任麻醉住院医师(2004-2007)，并在哈佛医学院波士顿儿童医院(Children‘s Hospital Boston，哈佛医学院)(2008)担任儿科麻醉师。从2008年起，我获得了麻醉学委员会认证。这次培训使我在基础科学和以病人为中心的临床工作方面奠定了坚实的基础。为了我的独立事业，我想把这两者结合起来。我特别感兴趣的是解决与儿童长期服用阿片类药物有关的临床挑战的问题，特别是关于长期接触吗啡的中枢适应的年龄依赖和长期后遗症。这是一个及时的话题，与儿科和麻醉的日常临床实践有很大的相关性。在…的背景下 除了K08奖，拟议的研究提供了在啮齿动物模型以及不同年龄段的儿童中获得功能磁共振相关方面的专业知识的机会。获得K08奖将极大地促进我的学术生涯，使我能够实现我的短期培训目标：通过使用功能磁共振成像技术在动物和人类神经成像方面的新培训领域扩展我的专业知识，并为成功的R01拨款申请培养技能。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。环境在建议的K08计划期间，我将听取David Borsook博士(导师)、Lino Becera博士(联合导师)、P.Ellen Grant博士(顾问)、Robert C.Tasker博士(顾问)和Kathryn G.Commons博士(顾问)的正式意见，以丰富我的研究经验，并获得新的技能和观点。这种导师和顾问的合作是帮助我作为一名经过必要的最先进培训的调查员实现独立的理想选择。拟议的研究将在波士顿儿童医院、马萨诸塞州综合医院和哈佛医学院的实验室和设施中进行。这些实验室中的每一个在与拟议研究的假设和具体目标相关的科学调查方面都有良好的记录。

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.