Respiratory depression and analgesia by opioid drugs in freely-behaving larval zebrafish

Abstract

An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.

Data availability

All data generated during this study are included in the manuscript. Source files are available.

Article and author information

Author details

  1. Shenhab Zaig

    Department of Medicine, Unity Health Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Carolina da Silveira Scarpellini

    Medicine, Unity Health Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5576-3468
  3. Gaspard Montandon

    Department of Medicine, Unity Health Toronto, Toronto, Canada
    For correspondence
    gaspard.montandon@utoronto.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3587-4472

Funding

St. Michael's Hospital Foundation (RIC)

  • Gaspard Montandon

J. P. Bickel Foundation (Medical Grant)

  • Gaspard Montandon

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

Ethics

Animal experimentation: The protocol was approved by the Animal Care Committee of St. Michael's Hospital. Protocol: ACC-811

Reviewing Editor

  1. Allan Basbaum, University of California San Francisco, United States

Publication history

  1. Received: September 23, 2020
  2. Accepted: March 11, 2021
  3. Accepted Manuscript published: March 15, 2021 (version 1)
  4. Version of Record published: April 21, 2021 (version 2)

Copyright

© 2021, Zaig 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. Shenhab Zaig
  2. Carolina da Silveira Scarpellini
  3. Gaspard Montandon
(2021)
Respiratory depression and analgesia by opioid drugs in freely-behaving larval zebrafish
eLife 10:e63407.
https://doi.org/10.7554/eLife.63407

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    Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations.

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    Results:

    Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis.

    Conclusions:

    Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant.

    Funding:

    Key Technological Projects of Guangdong Province grant 2018B030335001.

    Clinical trial number:

    NCT05265806

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