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.

项目摘要 培训计划：该提案描述了针对5年研究培训计划的问题 在镇痛机制中开发独立研究者。首席研究员是 哈佛医学院（HMS）麻醉教练和马萨诸塞州的一名教师麻醉师 综合医院（MGH），具有心血管生理和麻醉电生理学的背景。 他的心理Emery N. Brown博士是HMS的Warren M. Zapol麻醉教授 马萨诸塞州大脑和认知科学系的计算神经科学 技术（MIT），HMS and MIT的健康科学与技术教授。他的院长博士 Mao是MGH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·基兹（Richard J. Kitz）教授。他是一个实用的董事会认证 麻醉师和疼痛医学专家目前都指导疼痛和MGH的分裂 翻译疼痛实验室。凭借指导的临床科学家研究职业发展奖， 首席研究人员将在慢性疼痛模型，系统神经科学和 翻译研究设计足以制定独立的研究计划。他会接受的 大脑和认知科学系的课程，哈佛公共卫生学院以及通过 哈佛催化剂及其研究培训将在MGH和MIT的实验室进行。长期 该建议的目的是为成功的独立职业研究做好准备 使用系统神经科学方法的镇痛机制。 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，即 阿片类药物成瘾的流行和相关的过量死亡使人复杂。神经多巴胺（DA）电路 可能是产生镇痛的承诺目标，同时还可以防止阿片类药物诱导的副作用，例如 恶心，呼吸抑郁和镇静，但是它们在疼痛中的作用知之甚少。我们的初步 研究表明，ᴅ苯丙胺等于废除热痛觉过敏中的吗啡 炎症性慢性疼痛的小鼠模型，以及在周围的DA神经元的选择性激活 灰色（PAG）产生镇痛。该项目的目的是阐明多巴胺能镇痛的作用 电路下降疼痛抑制。结合药物和选择性神经回路 调制技术，我们将探测PAG多巴胺的行为，镇痛和奖励性能 临床意义的炎症性疼痛模型中的电路。了解多巴胺如何调节 特工营救疼痛可能会导致有效的新疼痛治疗。