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阿片类药物通过脑干的两个小区域抑制呼吸。

Opioids depress breathing through two small brainstem sites.

作者信息

Bachmutsky Iris, Wei Xin Paul, Kish Eszter, Yackle Kevin

机构信息

Department of Physiology, University of California-San Francisco, San Francisco, United States.

Neuroscience Graduate Program, University of California-San Francisco, San Francisco, United States.

出版信息

Elife. 2020 Feb 19;9:e52694. doi: 10.7554/eLife.52694.

DOI:10.7554/eLife.52694
PMID:32073401
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7077984/
Abstract

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose- opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem's breathing circuitry which we confirm by locally eliminating the µ-Opioid receptor. We find the critical brain site is the preBötzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

摘要

1999年至2017年间，美国阿片类药物过量使用率增长了四倍，达到了惊人的每天130例死亡。这种健康危机需要创新解决方案，这就要求揭示介导过量使用阿片类药物导致呼吸抑制的关键脑区和细胞类型。在这里，我们确定了给小鼠使用阿片类药物后呼吸的两个主要变化。这些变化涉及脑干呼吸回路，我们通过局部消除μ-阿片受体来证实这一点。我们发现关键脑区是前包钦格复合体，呼吸节律起源于此，并使用基因工具揭示该区域仅70 - 140个神经元就决定了其对阿片类药物的敏感性。对这些神经元的进一步表征可能会带来新的治疗方法，既能预防呼吸抑制，又能保留镇痛效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/8b0ddfb6edaa/elife-52694-resp-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/8a19249ea58d/elife-52694-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/9d9e2550c7c9/elife-52694-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/bcee10625c59/elife-52694-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/2ebdea2dca07/elife-52694-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/bc799de0a4c5/elife-52694-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/aec12f4f5e91/elife-52694-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/9773a99d2b13/elife-52694-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/d0212880b118/elife-52694-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/6cb6e0a6838c/elife-52694-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/72948a3ddd8b/elife-52694-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/bc5d8fe33e06/elife-52694-fig3-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/89e64cd575a9/elife-52694-fig3-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/a42de8498233/elife-52694-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/851cd49e3cd3/elife-52694-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/2d74ba294537/elife-52694-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/2d67e47ef875/elife-52694-fig4-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/8c93cd30b567/elife-52694-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/8b0ddfb6edaa/elife-52694-resp-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/8a19249ea58d/elife-52694-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/9d9e2550c7c9/elife-52694-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/bcee10625c59/elife-52694-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/2ebdea2dca07/elife-52694-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/bc799de0a4c5/elife-52694-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/aec12f4f5e91/elife-52694-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/9773a99d2b13/elife-52694-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/d0212880b118/elife-52694-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/6cb6e0a6838c/elife-52694-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/72948a3ddd8b/elife-52694-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/bc5d8fe33e06/elife-52694-fig3-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/89e64cd575a9/elife-52694-fig3-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/a42de8498233/elife-52694-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/851cd49e3cd3/elife-52694-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/2d74ba294537/elife-52694-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/2d67e47ef875/elife-52694-fig4-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/8c93cd30b567/elife-52694-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/410e/7077984/8b0ddfb6edaa/elife-52694-resp-fig2.jpg

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引用本文的文献

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[6]
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[7]
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[8]
Asymmetric neuromodulation in the respiratory network contributes to rhythm and pattern generation.

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[9]
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[10]
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本文引用的文献

[1]
Differential impact of two critical respiratory centres in opioid-induced respiratory depression in awake mice.

J Physiol. 2020-1

[2]
Biophysical mechanisms in the mammalian respiratory oscillator re-examined with a new data-driven computational model.

Elife. 2019-3-25

[3]
Drug and Opioid-Involved Overdose Deaths - United States, 2013-2017.

MMWR Morb Mortal Wkly Rep. 2018-1-4

[4]
The parafacial respiratory group and the control of active expiration.

Respir Physiol Neurobiol. 2018-6-19

[5]
The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception.

Br J Pharmacol. 2018-5-14

[6]
Defining preBötzinger Complex Rhythm- and Pattern-Generating Neural Microcircuits In Vivo.

Neuron. 2016-8-3

[7]
Interactions between respiratory oscillators in adult rats.

Elife. 2016-6-14

[8]
Voltage-Dependent Rhythmogenic Property of Respiratory Pre-Bötzinger Complex Glutamatergic, Dbx1-Derived, and Somatostatin-Expressing Neuron Populations Revealed by Graded Optogenetic Inhibition.

eNeuro. 2016-6-3

[9]
Two Pairs of ON and OFF Retinal Ganglion Cells Are Defined by Intersectional Patterns of Transcription Factor Expression.

Cell Rep. 2016-5-31

[10]
Increases in Drug and Opioid Overdose Deaths--United States, 2000-2014.

MMWR Morb Mortal Wkly Rep. 2016-1-1

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