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: 9068903
• 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/9068903
• 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; Behavioral; Bilateral; Boston; Brain; Chicago; Child; Childhood; Chronic; Clinical; Clinical Investigator Award; Collaborations; Complex; Critical Illness; Data; 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; Health; Hospitals; Human; Illinois; Immune response; Immunohistochemistry; Incidence; Infant; Inflammatory Response; 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 Deficit; Neuronal Plasticity; Newborn Infant; Opiate Addiction; 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; anxiety-related behavior; behavior measurement; behavior test; behavioral response; biological adaptation to stress; brain volume; career; clinical practice; cognitive development; cohort; drug seeking behavior; experience; improved; inflammatory marker; interest; laboratory facility; medical schools; motor impairment; neonate; neurochemistry; neuroimaging; novel; opiate tolerance; patient oriented; post-doctoral training; postnatal; prospective; pup; respiratory distress syndrome; 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。即使在没有疼痛的情况下，重症新生儿和儿童也会接受长时间的阿片类药物，以减轻焦虑，躁动，压力反应并促进通风。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延迟，神经认知和运动障碍有关。这表明早期产后阿片类药物治疗有神经途径发生重大改变的风险。研究表明，成年患者长期阿片类药物暴露后，杏仁核体积和连通性的剂量相关显着降低。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。但是，阿片类药物对杏仁核在发育中的大脑及其可能的长期负面影响的影响尚不清楚。我们假设在新生儿期间长时间的吗啡暴露将导致杏仁核和生活中相关结构的体积和连通性显着降低，而与未暴露于吗啡直到青春期或成年的受试者相比。这样的发现可能意味着对吗啡的成瘾品质可能敏感。该提议在转化努力方面是独一无二的，旨在使用神经影像，行为和免疫组织化学技术（AIM 1）以及使用神经影像学的儿童使用神经影像学，行为和免疫组织化学技术来定义不同年龄大鼠长期暴露的影响（AIM 2）。大鼠和儿童的功能磁共振成像（fMRI）将允许对长时间的吗啡给药及其长期影响进行翻译系统水平研究。作为AIM 1的一部分，将使用神经化学标记和行为测试对杏仁核中阿片类药物诱导的神经可塑性进行机械检查，以定义吗啡作用中神经胶质作用的统治。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能够转化。它将代表未来长期的基础 研究目的：寻找一种新型的年龄特异性辅助疗法，以最大程度地减少长期给药的长期后遗症。候选人。 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年），我目前是一名儿科麻醉师。截至2008年，我获得了麻醉学的董事会认证。这项培训使我能够在基础科学和以患者为导向的临床工作中建立强大的背景。在我的独立职业中，我想将两者聚集在一起。我特别有兴趣解决与儿童慢性阿片类药物给药引起的有关临床挑战有关的问题，尤其是关于年龄依赖性和长期后遗症的中央适应性后遗症，以长期暴露吗啡。这是一个与儿科和麻醉的日常临床实践相关的及时主题。在 拟议的研究是K08奖，为在啮齿动物模型以及不同年龄的儿童中获得fMRI相关方面的专业知识提供了机会。获得K08奖将通过允许我实现短期培训目标来大大提高我的学术生涯：通过使用fMRI进行动物和人类神经影像学培训的新培训领域扩大我的专业知识，并为成功的R01赠款应用程序开发技能。我的长期目标是获得临床医生/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计划中，我将获得DRS的正式意见。 David Borsook（导师），Lino Becerra（联合学），P。EllenGrant（顾问），Robert C. Tasker（顾问）和Kathryn G. Commons（顾问），以使我的研究经验多样化并获得新的技能和观点。这项导师和顾问的合作非常适合我作为必要的最先进培训的调查员独立。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都有与拟议研究的假设和具体目的有关的科学研究的良好往绩。