ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression

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Abstract

Opioids are perhaps the most effective analgesics in medicine. However, between 1999 to 2018, over 400,000 people in the United States died from opioid overdose. Excessive opioids make breathing lethally slow and shallow, a side-effect called opioid induced respiratory depression. This doubled-edged sword has sparked the desire to develop novel therapeutics that provide opioid-like analgesia without depressing breathing. One such approach has been the design of so-called 'biased agonists' that signal through some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced ß-arrestin 2 dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the 'biased agonist' approach, we re-examined breathing in ß-arrestin 2 deficient mice and instead find no connection between ß-arrestin 2 and opioid respiratory depression. This result suggests that any attenuated effect of 'biased agonists' on breathing is through an as-yet defined mechanism.

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The data generated in Figures 2-4 are provided in the source files.

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Iris Bachmutsky

Department of Physiology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Xin Paul Wei

Department of Physiology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Adelae Durand

Department of Physiology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Kevin Yackle

Department of Physiology, University of California, San Francisco, San Francisco, United States

For correspondence
Kevin.Yackle@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1870-2759

Funding

NIH Office of the Director (DP5-OD023116)

Kevin Yackle

Program for Breakthrough Biomedical Research

Kevin Yackle

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 animal experiments were performed in accordance with national and institutional guidelines with standard precautions to minimize animal stress and the number of animals used in each experiment. All animal protocols have been approved by the UCSF 'Office of Research'.approval number AN181239.

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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.