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Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms

Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kölliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respi...

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Autores principales: Bateman, Jordan T, Levitt, Erica S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10317500/
https://www.ncbi.nlm.nih.gov/pubmed/37314062
http://dx.doi.org/10.7554/eLife.81119
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author Bateman, Jordan T
Levitt, Erica S
author_facet Bateman, Jordan T
Levitt, Erica S
author_sort Bateman, Jordan T
collection PubMed
description Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kölliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons are unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the preBötzinger complex (preBötC) and rostral ventral respiratory group (rVRG). These medullary-projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBötC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. Surprisingly, the majority of excitatory preBötC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids, suggesting a selective opioid-sensitive circuit from the KF to the ventrolateral medulla. Opioids inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms—somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla—all of which could contribute to opioid-induced respiratory depression.
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spelling pubmed-103175002023-07-04 Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms Bateman, Jordan T Levitt, Erica S eLife Neuroscience Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kölliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons are unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the preBötzinger complex (preBötC) and rostral ventral respiratory group (rVRG). These medullary-projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBötC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. Surprisingly, the majority of excitatory preBötC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids, suggesting a selective opioid-sensitive circuit from the KF to the ventrolateral medulla. Opioids inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms—somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla—all of which could contribute to opioid-induced respiratory depression. eLife Sciences Publications, Ltd 2023-06-14 /pmc/articles/PMC10317500/ /pubmed/37314062 http://dx.doi.org/10.7554/eLife.81119 Text en © 2023, Bateman and Levitt https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Bateman, Jordan T
Levitt, Erica S
Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
title Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
title_full Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
title_fullStr Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
title_full_unstemmed Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
title_short Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
title_sort opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10317500/
https://www.ncbi.nlm.nih.gov/pubmed/37314062
http://dx.doi.org/10.7554/eLife.81119
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