The Role of Periaqueductal Gray Dopamine Neurons in Analgesia

导水管周围灰色多巴胺神经元在镇痛中的作用

• 批准号: 9385893
• 负责人: Norman Taylor
• 金额: $ 15.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2018-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385893
• 关键词: Absence of pain sensation; Adopted; Adverse effects; Affective; Alpha Cell; Analgesics; Anesthesia procedures; Anesthetics; Attention deficit hyperactivity disorder; Behavioral; Brain; Cannabinoids; Cardiovascular Physiology; Chronic inflammatory pain; Clinical; Cognitive Science; Critical Care; Data; Development; Dextroamphetamine; Dopamine; Electrophysiology (science); Epidemic; Faculty; General Hospitals; Glutamates; Goals; Health Sciences; Health Technology; Human; In Vitro; Institutes; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Lateral; Lead; Massachusetts; Mediating; Medicine; Mentors; Methylphenidate; Modeling; Morphine; Mus; Nausea; Neurons; Neurosciences; Neurosciences Research; Nociception; Nucleus Accumbens; Opiate Addiction; Opioid; Pain; Pain management; Pharmaceutical Preparations; Pharmacology; Play; Population; Principal Investigator; Productivity; Program Development; Property; Public Health; Public Health Schools; Recording of previous events; Research; Research Design; Research Personnel; Research Training; Rewards; Role; Scientist; Sedation procedure; Signal Transduction; Specialist; Spinal Cord; Spinal cord posterior horn; System; Techniques; Technology; Testing; Thermal Hyperalgesias; Training; Translational Research; Ventilatory Depression; Workplace; addiction; base; career; catalyst; chronic pain; clinically significant; combat; computational neuroscience; designer receptors exclusively activated by designer drugs; dopaminergic neuron; economic impact; experience; in vivo; inflammatory pain; innovation; innovative technologies; instructor; medical schools; midbrain central gray substance; mouse model; neural circuit; neuronal circuitry; novel; novel strategies; opioid use; overdose death; pain inhibition; prevent; professor; programs; psychostimulant; relating to nervous system; respiratory; skills; spinal pathway; theories; treatment planning

PROJECT SUMMARY Training Plan: This proposal describes a mentored 5-year research training program for the development of an independent investigator in analgesic mechanisms. The Principal Investigator is an Instructor of Anaesthesia at Harvard Medical School (HMS) and a faculty anesthesiologist at Massachusetts General Hospital (MGH), with a background in cardiovascular physiology and anesthetic electrophysiology. His mentor, Dr. Emery N. Brown, is Warren M. Zapol Professor of Anaesthesia at HMS, Professor of Computational Neuroscience in the Dept. of Brain and Cognitive Sciences at the Massachusetts Institute of Technology (MIT), and Professor of Health Sciences and Technology at HMS and MIT. His Co-Mentor, Dr. Mao, is the Vice Chair for Research in the Department of Anesthesia, Critical Care and Pain Medicine at MGH and the Richard J. Kitz Professor of Anesthesia Research at HMS. He is a practicing board-certified anesthesiologist and Pain Medicine Specialist who currently directs both the Division of Pain as well as MGH's translational pain laboratory. With the Mentored Clinical Scientist Research Career Development Award, the Principal Investigator will acquire new knowledge and skills in chronic pain models, systems neuroscience and translational research study design sufficient to develop an independent research program. He will take courses in the Dept. of Brain and Cognitive Sciences at MIT, the Harvard School of Public Health and through the Harvard Catalyst and his research training will take place in laboratories at MGH and MIT. The long-term objective of this proposal is to prepare the Principal Investigator for a successful independent career studying analgesic mechanisms using a systems neuroscience approach. Research Plan: The treatment of chronic pain remains a significant public health problem, which is compounded by the epidemic of opioid addiction and related overdose deaths. Neural dopamine (DA) circuits may be a promising target to produce analgesia, while also preventing opioid-induced side effects such as nausea, respiratory depression and sedation, but their role in pain is poorly understood. Our preliminary studies demonstrate that ᴅ-amphetamine is equipotent to morphine in abolishing thermal hyperalgesia in a mouse model of inflammatory chronic pain, and that selective activation of DA neurons in the periaqueductal gray (PAG) produces analgesia. The goal of this project is to elucidate the role of dopaminergic analgesic circuits on descending pain inhibition. Using a combination of pharmacological and selective neural circuit modulation techniques, we will probe the behavioral, analgesic, and rewarding properties of PAG dopamine circuits in clinically significant mouse models of inflammatory pain. Understanding how dopamine modulating agents relieve pain may lead to effective new pain treatments.

项目总结 培训计划：本提案描述了一项指导性的为期5年的研究培训计划 在止痛机制方面发展一个独立的研究人员。首席调查员是 哈佛医学院麻醉学讲师、马萨诸塞州麻醉师 综合医院(MGH)，具有心血管生理学和麻醉电生理学背景。 他的导师，埃默里·N·布朗博士，是HMS的沃伦·M·扎波尔麻醉学教授， 计算神经科学系。麻省理工学院脑与认知科学教授 他是麻省理工学院(MIT)健康科学与技术学教授。他的另一位导师，Dr。 毛是麻省理工学院麻醉、重症监护和疼痛医学系的研究副主席 以及HMS麻醉研究的理查德·J·基茨教授。他是一名持有执业资格证书的执业律师 麻醉师和疼痛医学专家，目前同时领导痛觉科和MGH 转化性疼痛实验室。凭借导师临床科学家研究职业发展奖， 首席研究员将在慢性疼痛模型、系统神经科学和 翻译研究性学习设计足以开发独立的研究项目。他会带上 系里的课程。麻省理工学院、哈佛大学公共卫生学院和 哈佛大学的催化剂和他的研究培训将在麻省理工学院和麻省理工学院的实验室进行。长期的 这项建议的目标是使首席调查员为成功的独立职业学习做好准备 使用系统神经科学方法的止痛机制。 研究计划：慢性疼痛的治疗仍然是一个重大的公共卫生问题，这是 再加上阿片成瘾流行和相关的过量死亡。神经多巴胺(DA)回路 可能是一个有希望的目标，以产生止痛，同时也防止阿片类药物引起的副作用，如 恶心、呼吸抑制和镇静，但它们在疼痛中的作用鲜为人知。我们的预赛 研究表明，ᴅ-苯丙胺在消除小鼠热痛觉过敏方面与吗啡相当。 小鼠慢性炎症性疼痛模型及选择性激活中脑导水管周围DA能神经元 Gray(PAG)产生止痛作用。这个项目的目标是阐明多巴胺能止痛剂的作用。 关于下行疼痛抑制的电路。使用药理和选择性神经回路的组合 调制技术，我们将探索PAG多巴胺的行为、镇痛和奖赏特性 临床上有意义的炎症性疼痛小鼠模型中的回路。了解多巴胺是如何调节的 止痛剂可能会带来有效的新的疼痛治疗方法。