Opioid effects on respiratory-controlling pontine neurons

阿片类药物对呼吸控制脑桥神经元的影响

• 批准号: 9037636
• 负责人: Erica Sawyer Levitt
• 金额: $ 8.95万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037636
• 关键词: Absence of pain sensation; Acute; Address; Adverse effects; Agonist; Area; Award; Brain; Brain Stem; Cause of Death; Cell Nucleus; Cessation of life; Chronic; Clinical; Complex; Consultations; Depressed mood; Development; Electrophysiology (science); Euphoria; Goals; Health; In Situ; Injection of therapeutic agent; Interneurons; Knowledge; Lead; Learning; Left; Life; Location; Measures; Mediating; Mentors; Mentorship; Methionine Enkephalin; Morphine; Narcotic Antagonists; Nerve; Neurons; Opiates; Opioid; Overdose; Pharmacology; Phase; Phenotype; Pontine structure; Population Heterogeneity; Positioning Attribute; Preparation; Productivity; Rattus; Receptor Activation; Regulation; Research; Research Personnel; Respiration; Respiratory physiology; Scientist; Serotonin Receptor 5-HT1A; Skills Development; Slice; Technical Expertise; Testing; Therapeutic; Therapeutic Intervention; Tracer; Training; Universities; Ventilatory Depression; Vocational Guidance; Withdrawal Symptom; Work; career; career development; desensitization; design; experience; extracellular; improved; in vivo; mu opioid receptors; neuroregulation; pain symptom; preBotzinger complex; presynaptic neurons; prevent; professor; receptor; research study; respiratory; skill acquisition; tenure track

 DESCRIPTION (provided by applicant): Death from opioid overdose is primarily due to respiratory depression, yet little is known about the cellular mechanisms of opioids on respiratory-controlling neurons. The long-term goal is to become an independent tenure-track investigator studying the mechanisms responsible for the respiratory depressant effects of opioids. This proposal has been designed to supplement the candidate's background in opioid pharmacology and brain slice electrophysiology and provide the additional knowledge and technical skills in respiratory physiology required to accomplish this goal. Opioids have been shown to suppress respiration through multiple areas of the central respiratory network, including the preBotzinger complex in the medulla and the Kolliker-Fuse (KF) nucleus in the pons. Although opioids have been shown to inhibit preBotzinger neurons, the mechanism of opioid actions in the KF has not been studied and is therefore unknown. The immediate goal of this proposal is to determine how opioids modulate KF neurons to alter respiration. The hypothesis is that opioids hyperpolarize KF neurons to disrupt the respiratory network. This hypothesis will be tested by recording (1) from KF neurons in brain slices and (2) from KF neurons and respiratory nerves in an in situ preparation with intact respiratory network and in vivo respiratory cycle. In Aim 1, extracellular recording from the in situ preparation will identif the respiratory phenotype of KF neurons inhibited by opioids. This new technical skill will be learned through consultation with Drs. Ana Abdala and Julian Paton (University of Bristol) and Mary Heinricher (OHSU) and will be a critical component of the candidate's career development. Given the lack of tolerance to the respiratory depressant effect of opioids, the hypothesis of Aim 2 is that there will be very little tolerance and desensitization of mu opioid receptors on KF neurons. The goal of Aim 3, which will be performed during the independent phase of this award, is to identify the location and function of 5-HT1A receptors that can reverse opioid-induced respiratory depression. A therapeutic strategy such as 5-HT1A agonists that can reverse respiratory depression, but leave analgesia intact would be a significant advance. Mentorship from John Williams, who is a world-renowned electro physiologist and has mentored over 20 scientists to achieve independent careers, will provide continued training in brain slice electrophysiology and development of skills to manage an independent research group. New knowledge in respiratory physiology will be acquired from co-mentor John Bissonnette (OHSU), who has over 30 years of experience in neural control of respiration. The new knowledge, technical skills, continued productivity and practical career guidance will place the candidate in competitive position to become a tenure-track assistant professor studying the respiratory depressant effects of opioids from a cellular and network perspective.

 描述（由申请人提供）：阿片类药物过量导致的死亡主要是由于呼吸抑制，但对阿片类药物对呼吸控制神经元的细胞机制知之甚少。长期目标是成为一名独立的终身研究员，研究阿片类药物对呼吸系统的影响。该提案旨在补充候选人在阿片类药物药理学和脑切片电生理学方面的背景，并提供实现这一目标所需的呼吸生理学方面的额外知识和技术技能。阿片类药物已被证明可通过中枢呼吸网络的多个区域抑制呼吸，包括延髓中的前博青格复合体和脑桥中的科利克-克拉（KF）核。虽然阿片类药物已被证明可以抑制preBotzinger神经元，但尚未研究KF中阿片类药物作用的机制，因此尚不清楚。该提案的直接目标是确定阿片类药物如何调节KF神经元以改变呼吸。假设是阿片类药物使KF神经元过度兴奋以破坏呼吸网络。将通过记录（1）脑切片中的KF神经元和（2）具有完整呼吸网络和体内呼吸周期的原位制备物中的KF神经元和呼吸神经来检验该假设。在目的1中，从原位制备的细胞外记录将识别阿片类药物抑制的KF神经元的呼吸表型。这一新的技能将通过与Ana Abdala和Julian Paton博士（布里斯托大学）和玛丽海因里希（OHSU）的协商来学习，并将成为候选人职业发展的关键组成部分。鉴于对阿片类药物的呼吸抑制作用缺乏耐受性，目标2的假设是KF神经元上的μ阿片受体将存在非常小的耐受性和脱敏。目标3将在该奖项的独立阶段进行，其目标是确定5-HT 1A受体的位置和功能，这些受体可以逆转阿片类药物诱导的呼吸抑制。一种治疗策略，如5-HT 1A激动剂，可以逆转呼吸抑制，但保持镇痛完整，将是一个重大的进步。约翰威廉姆斯，谁是世界著名的电生理学家，并指导了20多名科学家实现独立的职业生涯，导师将提供脑切片电生理学和技能的发展，以管理一个独立的研究小组的持续培训。呼吸生理学的新知识将从共同导师John Bissonnette（OHSU）那里获得，他在呼吸神经控制方面拥有30多年的经验。新的知识，技术技能，持续的生产力和实际的职业指导将使候选人处于竞争地位，成为终身助理教授，从细胞和网络的角度研究阿片类药物的呼吸抑制作用。