Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
- University of Florida, United States
- University of Michigan-Ann Arbor, United States
Abstract
Opioids depress breathing by inhibition of inter-connected 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 pre-Bötzinger 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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Data generated or analyzed during this study are included in the manuscript and supporting files.
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Author details
Funding
National Institute on Drug Abuse (R01DA047978)
- Erica S Levitt
National Institute on Drug Abuse (F31DA053798)
- Jordan T Bateman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee at the University of Florida (protocol #09515) and were in agreement with the National Institutes of Health "Guide for the Care and Use of Laboratory Animals."
Copyright
© 2023, Bateman & Levitt
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms
eLife 12:e81119.
https://doi.org/10.7554/eLife.81119
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