Opioids modulate an emergent rhythmogenic process to depress breathing

  1. Xiaolu Sun
  2. Carolina Thörn Pérez
  3. Nagaraj Halemani D
  4. Xuesi Max Shao
  5. Morgan Greenwood
  6. Sarah Heath
  7. Jack L Feldman
  8. Kaiwen Kam  Is a corresponding author
  1. University of California, Los Angeles, United States
  2. Rosalind Franklin University of Medicine and Science, United States

Abstract

How mammalian neural circuits generate rhythmic activity in motor behaviors, such as breathing, walking, and chewing, remains elusive. For breathing, rhythm generation is localized to a brainstem nucleus, the preBötzinger Complex (preBötC). Rhythmic preBötC population activity consists of strong inspiratory bursts, which drive motoneuronal activity, and weaker burstlets, which we hypothesize reflects an emergent rhythmogenic process. If burstlets underlie inspiratory rhythmogenesis, respiratory depressants, such as opioids, should reduce burstlet frequency. Indeed, in medullary slices from neonatal mice, the μ-opioid receptor (μOR) agonist DAMGO slowed burstlet generation. Genetic deletion of μORs in a glutamatergic preBötC subpopulation abolished opioid-mediated depression, and the neuropeptide Substance P, but not blockade of inhibitory synaptic transmission, reduced opioidergic effects. We conclude that inspiratory rhythmogenesis is an emergent process, modulated by opioids, that does not rely on strong bursts of activity associated with motor output. These findings also point to strategies for ameliorating opioid-induced depression of breathing.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files are available at sites.google.com/site/kwkamlab.

Article and author information

Author details

  1. Xiaolu Sun

    Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Carolina Thörn Pérez

    Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nagaraj Halemani D

    Department of Cell Biology and Anatomy, Rosalind Franklin University of Medicine and Science, North Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xuesi Max Shao

    Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5165-347X
  5. Morgan Greenwood

    RFUMS/DePaul Research Internship Program, Rosalind Franklin University of Medicine and Science, North Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sarah Heath

    Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jack L Feldman

    Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3692-9412
  8. Kaiwen Kam

    Department of Cell Biology and Anatomy, Rosalind Franklin University of Medicine and Science, North Chicago, United States
    For correspondence
    kaiwen.kam@rosalindfranklin.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8479-0542

Funding

National Institutes of Health (NS072211)

  • Jack L Feldman

National Institutes of Health (HL135779)

  • Jack L Feldman

National Institutes of Health (NS097492)

  • Kaiwen Kam

Vetenskapsrådet

  • Carolina Thörn Pérez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experimental procedures were carried out in accordance with the United States Public Health Service and Institute for Laboratory Animal Research Guide for the Care and Use of Laboratory Animals. All of the animals were handled according to approved institutional protocols at the University of California, Los Angeles (#1994-159-83P) and Rosalind Franklin University of Medicine and Science (#B14-16, #B18-10). All protocols were approved by University of California Animal Research Committee (Animal Welfare Assurance #A3196-01) and the Rosalind Franklin University of Medicine and Science Institutional Animal Care and Use Committee (Animal Welfare Assurance #A3279-01). Every effort was made to minimize pain and discomfort, as well as the number of animals.

Reviewing Editor

  1. Ronald L Calabrese, Emory University, United States

Publication history

  1. Received: July 27, 2019
  2. Accepted: December 11, 2019
  3. Accepted Manuscript published: December 16, 2019 (version 1)
  4. Version of Record published: December 31, 2019 (version 2)

Copyright

© 2019, Sun et al.

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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  1. Xiaolu Sun
  2. Carolina Thörn Pérez
  3. Nagaraj Halemani D
  4. Xuesi Max Shao
  5. Morgan Greenwood
  6. Sarah Heath
  7. Jack L Feldman
  8. Kaiwen Kam
(2019)
Opioids modulate an emergent rhythmogenic process to depress breathing
eLife 8:e50613.
https://doi.org/10.7554/eLife.50613

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