Opioids modulate an emergent rhythmogenic process to depress breathing
- University of California, Los Angeles, United States
- 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
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.
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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Opioids modulate an emergent rhythmogenic process to depress breathing
eLife 8:e50613.
https://doi.org/10.7554/eLife.50613
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