Neural basis of opioid-induced respiratory depression
阿片类药物引起的呼吸抑制的神经基础
基本信息
- 批准号:10323043
- 负责人:
- 金额:$ 34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAnalgesicsAreaAttenuatedBehaviorBehavioralBrainBrain StemBreathingCause of DeathCell NucleusChemoreceptorsChronicComplexConflict (Psychology)DataDoseElectrophysiology (science)Functional disorderGlutamatesGoalsLateralMaintenanceMeasuresMediatingMorphineMusNeuronsOpioidOpioid ReceptorPhasePlethysmographyPontine structurePopulationPreparationPresynaptic ReceptorsPublic HealthReflex actionRegulationRespiratory CenterRespiratory FailureRespiratory SystemRoleSliceSynapsesTestingTracerVentilatory Depressionawakebasebrain circuitrydesensitizationexperimental studyexpirationextracellularin vivoinnovationlocus ceruleus structuremature animalmu opioid receptorsneural circuitopioid mortalityopioid overdoseopioid useoptogeneticspreBotzinger complexpresynapticreceptorreceptor sensitivityrelating to nervous systemrespiratory
项目摘要
Death from opioid overdose is primarily due to respiratory depression, yet little is known of the cellular
mechanisms of opioids on respiratory-controlling neurons. Breathing is controlled by a highly interconnected
network of neurons in the brainstem. Opioid-induced respiratory depression is due to activation of mu opioid
receptors located throughout in the brainstem respiratory network, including the Kölliker-Fuse (KF) in the
pons and respiratory control areas in the medulla. There are conflicting results regarding the importance of
these areas in opioid-induced respiratory depression. Based on preliminary data, we propose that opioids act
on the respiratory network collectively to cause respiratory depression rather than one area in isolation. There
are major voids in the understanding of opioid modulation of the respiratory circuitry, especially inhibition of
transmitter release. The goal of this proposal is to determine opioid regulation of identified projections
between respiratory controlling brainstem neurons in adult mice with fully developed respiratory circuitry. It
will focus on three brainstem areas that express mu opioid receptors and have dense reciprocal projections: the
preBötzinger complex and Bötzinger complex in the medulla and the KF in the pons. The hypothesis is that
presynaptic opioid receptors regulate synaptic connections between these areas to mediate opioid-induced
respiratory depression. A combination of approaches will be used to test this hypothesis on the cellular, circuit
and behavioral level. In Aim 1, opioid regulation of excitatory projections from the KF to the medulla will be
defined using brain slice electrophysiology and optogenetics. Then, in vivo experiments will test the role of
projections to the medulla in mediating respiratory depression caused by systemic opioid administration in
awake adult animals. In Aim 2, the opioid sensitivity of synapses from medullary projection neurons onto KF
neurons will be determined using brain slice electrophysiology and optogenetics. A unique arterially perfused
preparation that maintains an intact brainstem and “in vivo-like” respiratory cycle will be used to determine if
medullary projection neurons control the activity of single KF neurons. In Aim 3, the vulnerability of
presynaptic mu opioid receptors in the KF to chronic opioid treatment will be determined using brain slice
electrophysiology. Results from this project will provide mechanistic detail on opioid control of the
pontomedullary respiratory circuitry that leads to respiratory depression. This may help identify strategies to
counter opioid-induced respiratory depression and also inform on how synaptic mechanisms affect behavior.
阿片类药物过量死亡主要是由于呼吸抑制,但对细胞内的情况知之甚少。
阿片类药物对呼吸控制神经元的作用机制。呼吸是由高度互联的
脑干中的神经元网络。阿片类药物引起的呼吸抑制是由于Mu阿片类药物激活所致
受体分布于脑干呼吸网络,包括脑干呼吸网络中的Kölliker-Fuse(KF)。
延髓中的桥脑和呼吸控制区。关于这一点的重要性,有相互矛盾的结果
这些区域中阿片类药物引起的呼吸抑制。根据初步数据,我们认为阿片类药物起作用
在呼吸网络上集体造成呼吸抑制,而不是孤立地在一个区域。那里
是理解阿片类药物对呼吸回路的调节的主要空白,特别是抑制
发射机释放。这项提案的目标是确定已确定的投射的阿片类药物调节。
在呼吸回路完全发达的成年小鼠的呼吸控制脑干神经元之间。它
将专注于三个表达u阿片受体并具有密集相互投射的脑干区域:
延髓的Prebötzinger复合体和Bötzinger复合体,脑桥的KF复合体。假设是这样的
突触前阿片受体调节这些区域之间的突触连接以介导阿片类药物诱导
呼吸抑制。一种方法的组合将被用来在细胞电路上检验这一假设。
和行为层面。在目标1中,从KF到延髓的兴奋性投射的阿片类调节将是
使用脑片电生理学和光遗传学来定义。然后,在体内实验将测试的作用
延髓投射在介导阿片类药物全身给药所致呼吸抑制中的作用
醒着的成年动物。在目标2中,来自延髓投射神经元的突触对KF的阿片敏感性
将使用脑片电生理学和光遗传学来确定神经元。一种独特的动脉灌流
保持完整的脑干和类似活体的呼吸周期的准备将用于确定
延髓投射神经元控制单个KF神经元的活动。在目标3中,
用脑片测定突触前MU阿片受体在KF对慢性阿片类药物治疗中的作用
电生理学。该项目的结果将提供阿片类药物控制的机械细节
导致呼吸抑制的脑桥延髓呼吸回路。这可能有助于确定战略,以
对抗阿片类药物诱导的呼吸抑制,并告知突触机制如何影响行为。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Erica Sawyer Levitt其他文献
Erica Sawyer Levitt的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Erica Sawyer Levitt', 18)}}的其他基金
Neural basis of opioid-induced respiratory depression
阿片类药物引起的呼吸抑制的神经基础
- 批准号:
9893844 - 财政年份:2019
- 资助金额:
$ 34万 - 项目类别:
Neural basis of opioid-induced respiratory depression
阿片类药物引起的呼吸抑制的神经基础
- 批准号:
10767055 - 财政年份:2019
- 资助金额:
$ 34万 - 项目类别:
Neural basis of opioid-induced respiratory depression
阿片类药物引起的呼吸抑制的神经基础
- 批准号:
10116353 - 财政年份:2019
- 资助金额:
$ 34万 - 项目类别:
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 - 财政年份:2015
- 资助金额:
$ 34万 - 项目类别:
Functional Interactions of Mu and Delta Opioid Receptors
Mu 和 Delta 阿片受体的功能相互作用
- 批准号:
7409483 - 财政年份:2008
- 资助金额:
$ 34万 - 项目类别:
Functional Interactions of Mu and Delta Opioid Receptors
Mu 和 Delta 阿片受体的功能相互作用
- 批准号:
7613402 - 财政年份:2008
- 资助金额:
$ 34万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 34万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 34万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 34万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 34万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 34万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 34万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 34万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 34万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 34万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 34万 - 项目类别:
Grant-in-Aid for Early-Career Scientists