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

吗啡对脑回路的立即和延迟影响：动物和人类的Cor

• 批准号: 8566922
• 负责人: DUSICA BAJIC
• 金额: $ 18.33万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566922
• 关键词: 1 year old; 12 year old; Address; Adolescence; Adolescent; Adult; Affective; Age; Age-Months; Agitation; Amygdaloid structure; Analgesics; Anesthesia procedures; Anesthesiology; Animal Model; Animals; Anisotropy; Anxiety; Applications Grants; Astrocytes; Attenuated; Award; Basic Science; Behavior; Behavioral; Bilateral; Boston; Brain; Chicago; Child; Childhood; Chronic; Clinical; Clinical Investigator Award; Cognitive; Collaborations; Complex; Critical Illness; Data; Dependence; Development; Diffusion Magnetic Resonance Imaging; Dimensions; Doctor of Philosophy; Dose; Emotional; Environment; Environmental air flow; Exposure to; Fellowship; Foundations; Fright; Functional Magnetic Resonance Imaging; Funding; Future; Gender; General Hospitals; Glial Fibrillary Acidic Protein; Goals; Grant; Growth; Hospitals; Human; Illinois; Immune response; Immunohistochemistry; Incidence; Infant; Inflammatory; Institution; Interleukin-1; Interleukin-6; Investigation; Knowledge; Laboratories; Language Development; Lead; Life; Long-Term Effects; Magnetic Resonance Imaging; Mainstreaming; Massachusetts; Memory; Mental disorders; Mentors; Microglia; Modeling; Moods; Morphine; Multimodal Imaging; Neonatal; Neural Pathways; Neuroanatomy; Neurocognitive; Neuronal Plasticity; Newborn Infant; Opioid; Pain; Pain management; Pathway interactions; Patients; Pediatric Hospitals; Pediatrics; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Process; Rattus; Recording of previous events; Reporting; Research; Research Personnel; Residencies; Rest; Risk; Rodent Model; Role; Running; Scanning; Scientist; Sedation procedure; Serbia; Structure; System; Techniques; Training; Translating; Translational Research; United States National Institutes of Health; Universities; Ursidae Family; Work; addiction; age related; behavior measurement; behavior test; biological adaptation to stress; brain volume; career; clinical practice; cohort; drug seeking behavior; experience; improved; inflammatory marker; interest; laboratory facility; medical schools; motor impairment; neonate; neurochemistry; neuroimaging; novel; patient oriented; post-doctoral training; postnatal; prospective; public health relevance; pup; respiratory distress syndrome; response; skills; stem; time interval; translational approach

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.

描述（由申请人提供）：研究。即使没有疼痛，危重新生儿和儿童也会长期接受阿片类药物镇静，以减少焦虑、烦躁、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。这表明产后早期阿片类药物治疗存在神经通路发生重大改变的风险。研究表明，成年患者长期接触阿片类药物后，杏仁核体积和连接性会出现与剂量相关的显着下降。杏仁核是一种复杂的结构，已知参与多个系统的调节，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，与直到青春期或成年才接触吗啡的受试者相比，在新生儿期长期接触吗啡将导致晚年杏仁核及相关结构的体积和连接性显着下降。这些发现意味着可能对吗啡的成瘾特性敏感。该提案的独特之处在于其转化努力，使用神经影像学、行为和免疫组织化学技术（AIM 1）以及使用神经影像学技术（AIM 2）来定义长期吗啡暴露对不同年龄的大鼠的影响。大鼠和儿童的功能磁共振成像（fMRI）将允许对长期吗啡给药及其长期影响进行转化系统水平的研究。作为 AIM 1 的一部分，将使用神经化学标记物和行为测试对阿片类药物诱导的杏仁核神经可塑性进行机械检查，以定义吗啡效应中神经胶质细胞作用的个体发育。最终，通过定义动物模型和人类相关模型，这项工作将为这一重大临床问题提供转化方法。它将为未来广泛的长期发展奠定基础 研究目标：寻找一种新颖的年龄特异性辅助疗法，以尽量减少早期长期服用吗啡造成的长期后遗症。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 年在伊利诺伊大学芝加哥分校获得药理学博士学位。我在同一机构（2000-2003 年）耶鲁大学麻醉住院医师实习接受了博士后培训耶鲁大学避风港医院 (2004-2007) 和哈佛医学院波士顿儿童医院小儿麻醉奖学金（2008），我目前担任儿科麻醉师。我于 2008 年获得了麻醉学委员会认证。这次培训使我在基础科学和以患者为导向的临床工作方面建立了强大的背景。对于我的独立职业生涯，我想将两者结合起来。我对解决与儿童长期使用阿片类药物引起的临床挑战相关的问题特别感兴趣，特别是关于长期吗啡暴露的中枢适应的年龄依赖性和长期后遗症。这是一个与儿科和麻醉日常临床实践密切相关的及时话题。在这样的背景下 K08 奖中，拟议的研究提供了在啮齿动物模型以及不同年龄的儿童中获得功能磁共振成像相关方面专业知识的机会。获得 K08 奖将极大地推进我的学术生涯，让我能够实现短期培训目标：通过使用 fMRI 进行动物和人类神经成像培训的新领域来扩展我的专业知识，并培养成功申请 R01 资助的技能。我的长期目标是获得作为临床医生/科学家的学术独立性并建立自己的研究团队。环境。在拟议的 K08 计划期间，我将收到 Drs. 的正式意见。 David Borsook（导师）、Lino Becerra（共同导师）、P. Ellen Grant（顾问）、Robert C. Tasker（顾问）和 Kathryn G. Commons（顾问），使我的研究经验多样化并获得新的技能和知识观点。导师和顾问的这种合作非常理想，可以帮助我通过必要的最先进的培训获得独立作为一名调查员。拟议的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。这些实验室中的每一个都在与拟议研究的假设和具体目标相关的科学研究方面拥有良好的记录。