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

Opioids are perhaps the most effective analgesics in medicine. However, between 1999 and 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-edge...

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Autores principales: Bachmutsky, Iris, Wei, Xin Paul, Durand, Adelae, Yackle, Kevin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213404/
https://www.ncbi.nlm.nih.gov/pubmed/34002697
http://dx.doi.org/10.7554/eLife.62552
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author Bachmutsky, Iris
Wei, Xin Paul
Durand, Adelae
Yackle, Kevin
author_facet Bachmutsky, Iris
Wei, Xin Paul
Durand, Adelae
Yackle, Kevin
author_sort Bachmutsky, Iris
collection PubMed
description Opioids are perhaps the most effective analgesics in medicine. However, between 1999 and 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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spelling pubmed-82134042021-06-21 ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression Bachmutsky, Iris Wei, Xin Paul Durand, Adelae Yackle, Kevin eLife Neuroscience Opioids are perhaps the most effective analgesics in medicine. However, between 1999 and 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. eLife Sciences Publications, Ltd 2021-05-18 /pmc/articles/PMC8213404/ /pubmed/34002697 http://dx.doi.org/10.7554/eLife.62552 Text en © 2021, Bachmutsky et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Bachmutsky, Iris
Wei, Xin Paul
Durand, Adelae
Yackle, Kevin
ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression
title ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression
title_full ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression
title_fullStr ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression
title_full_unstemmed ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression
title_short ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression
title_sort ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213404/
https://www.ncbi.nlm.nih.gov/pubmed/34002697
http://dx.doi.org/10.7554/eLife.62552
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