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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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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. |
format | Online Article Text |
id | pubmed-8213404 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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