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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Main Authors: Nicholas J. Malcolm, Barbara Palkovic, Daniel J. Sprague, Maggie M. Calkins, Janelle K. Lanham, Adam L. Halberstadt, Astrid G. Stucke, John D. McCorvy
Format: Article
Language:English
Published: Elsevier 2023-07-01
Series:iScience
Subjects:
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.
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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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AT danieljsprague muopioidreceptorselectivesuperagonistsproduceprolongedrespiratorydepression
AT maggiemcalkins muopioidreceptorselectivesuperagonistsproduceprolongedrespiratorydepression
AT janelleklanham muopioidreceptorselectivesuperagonistsproduceprolongedrespiratorydepression
AT adamlhalberstadt muopioidreceptorselectivesuperagonistsproduceprolongedrespiratorydepression
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