Mu-opioid receptor selective superagonists produce prolonged respiratory depression
Summary: Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) μ-opioid receptor (MOR), which signals through G protein-dependent and β-arrestin pathways. Using a bioluminescence resonance ene...
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Format: | Article |
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Elsevier
2023-07-01
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Series: | iScience |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223011987 |
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author | Nicholas J. Malcolm Barbara Palkovic Daniel J. Sprague Maggie M. Calkins Janelle K. Lanham Adam L. Halberstadt Astrid G. Stucke John D. McCorvy |
author_facet | Nicholas J. Malcolm Barbara Palkovic Daniel J. Sprague Maggie M. Calkins Janelle K. Lanham Adam L. Halberstadt Astrid G. Stucke John D. McCorvy |
author_sort | Nicholas J. Malcolm |
collection | DOAJ |
description | Summary: Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) μ-opioid receptor (MOR), which signals through G protein-dependent and β-arrestin pathways. Using a bioluminescence resonance energy transfer (BRET) system, we investigate GPCR-signaling profiles by synthetic nitazenes, which are known to cause overdose and death due to respiratory depression. We show that isotonitazene and its metabolite, N-desethyl isotonitazene, are very potent MOR-selective superagonists, surpassing both DAMGO G protein and β-arrestin recruitment activity, which are properties distinct from other conventional opioids. Both isotonitazene and N-desethyl isotonitazene show high potency in mouse analgesia tail-flick assays, but N-desethyl isotonitazene shows longer-lasting respiratory depression compared to fentanyl. Overall, our results suggest that potent MOR-selective superagonists may be a pharmacological property predictive of prolonged respiratory depression resulting in fatal consequences and should be examined for future opioid analgesics. |
first_indexed | 2024-03-12T22:23:17Z |
format | Article |
id | doaj.art-fc293bbf9b694c2ca0a05e1bba69bdbb |
institution | Directory Open Access Journal |
issn | 2589-0042 |
language | English |
last_indexed | 2024-03-12T22:23:17Z |
publishDate | 2023-07-01 |
publisher | Elsevier |
record_format | Article |
series | iScience |
spelling | doaj.art-fc293bbf9b694c2ca0a05e1bba69bdbb2023-07-23T04:55:37ZengElsevieriScience2589-00422023-07-01267107121Mu-opioid receptor selective superagonists produce prolonged respiratory depressionNicholas J. Malcolm0Barbara Palkovic1Daniel J. Sprague2Maggie M. Calkins3Janelle K. Lanham4Adam L. Halberstadt5Astrid G. Stucke6John D. McCorvy7Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA; Research Service, VA San Diego Healthcare System, San Diego, CA 92108, USADepartment of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Corresponding authorSummary: Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) μ-opioid receptor (MOR), which signals through G protein-dependent and β-arrestin pathways. Using a bioluminescence resonance energy transfer (BRET) system, we investigate GPCR-signaling profiles by synthetic nitazenes, which are known to cause overdose and death due to respiratory depression. We show that isotonitazene and its metabolite, N-desethyl isotonitazene, are very potent MOR-selective superagonists, surpassing both DAMGO G protein and β-arrestin recruitment activity, which are properties distinct from other conventional opioids. Both isotonitazene and N-desethyl isotonitazene show high potency in mouse analgesia tail-flick assays, but N-desethyl isotonitazene shows longer-lasting respiratory depression compared to fentanyl. Overall, our results suggest that potent MOR-selective superagonists may be a pharmacological property predictive of prolonged respiratory depression resulting in fatal consequences and should be examined for future opioid analgesics.http://www.sciencedirect.com/science/article/pii/S2589004223011987Cellular neuroscienceMolecular neuroscienceNeuroscience |
spellingShingle | Nicholas J. Malcolm Barbara Palkovic Daniel J. Sprague Maggie M. Calkins Janelle K. Lanham Adam L. Halberstadt Astrid G. Stucke John D. McCorvy Mu-opioid receptor selective superagonists produce prolonged respiratory depression iScience Cellular neuroscience Molecular neuroscience Neuroscience |
title | Mu-opioid receptor selective superagonists produce prolonged respiratory depression |
title_full | Mu-opioid receptor selective superagonists produce prolonged respiratory depression |
title_fullStr | Mu-opioid receptor selective superagonists produce prolonged respiratory depression |
title_full_unstemmed | Mu-opioid receptor selective superagonists produce prolonged respiratory depression |
title_short | Mu-opioid receptor selective superagonists produce prolonged respiratory depression |
title_sort | mu opioid receptor selective superagonists produce prolonged respiratory depression |
topic | Cellular neuroscience Molecular neuroscience Neuroscience |
url | http://www.sciencedirect.com/science/article/pii/S2589004223011987 |
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