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Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism

Delta (DOR) and mu opioid receptors (MOR) can complex as heteromers, conferring functional properties in agonist binding, signaling and trafficking that can differ markedly from their homomeric counterparts. Because of these differences, DOR/MOR heteromers may be a novel therapeutic target in the tr...

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Autores principales: Milan-Lobo, Laura, Enquist, Johan, van Rijn, Richard M., Whistler, Jennifer L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598907/
https://www.ncbi.nlm.nih.gov/pubmed/23554887
http://dx.doi.org/10.1371/journal.pone.0058362
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author Milan-Lobo, Laura
Enquist, Johan
van Rijn, Richard M.
Whistler, Jennifer L.
author_facet Milan-Lobo, Laura
Enquist, Johan
van Rijn, Richard M.
Whistler, Jennifer L.
author_sort Milan-Lobo, Laura
collection PubMed
description Delta (DOR) and mu opioid receptors (MOR) can complex as heteromers, conferring functional properties in agonist binding, signaling and trafficking that can differ markedly from their homomeric counterparts. Because of these differences, DOR/MOR heteromers may be a novel therapeutic target in the treatment of pain. However, there are currently no ligands selective for DOR/MOR heteromers, and, consequently, their role in nociception remains unknown. In this study, we used a pharmacological opioid cocktail that selectively activates and stabilizes the DOR/MOR heteromer at the cell surface by blocking its endocytosis to assess its role in antinociception. We found that mice treated chronically with this drug cocktail showed a significant right shift in the ED(50) for opioid-mediated analgesia, while mice treated with a drug that promotes degradation of the heteromer did not. Furthermore, promoting degradation of the DOR/MOR heteromer after the right shift in the ED(50) had occurred, or blocking signal transduction from the stabilized DOR/MOR heteromer, shifted the ED(50) for analgesia back to the left. Taken together, these data suggest an anti-analgesic role for the DOR/MOR heteromer in pain. In conclusion, antagonists selective for DOR/MOR heteromer could provide an avenue for alleviating reduced analgesic response during chronic pain treatment.
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spelling pubmed-35989072013-04-02 Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism Milan-Lobo, Laura Enquist, Johan van Rijn, Richard M. Whistler, Jennifer L. PLoS One Research Article Delta (DOR) and mu opioid receptors (MOR) can complex as heteromers, conferring functional properties in agonist binding, signaling and trafficking that can differ markedly from their homomeric counterparts. Because of these differences, DOR/MOR heteromers may be a novel therapeutic target in the treatment of pain. However, there are currently no ligands selective for DOR/MOR heteromers, and, consequently, their role in nociception remains unknown. In this study, we used a pharmacological opioid cocktail that selectively activates and stabilizes the DOR/MOR heteromer at the cell surface by blocking its endocytosis to assess its role in antinociception. We found that mice treated chronically with this drug cocktail showed a significant right shift in the ED(50) for opioid-mediated analgesia, while mice treated with a drug that promotes degradation of the heteromer did not. Furthermore, promoting degradation of the DOR/MOR heteromer after the right shift in the ED(50) had occurred, or blocking signal transduction from the stabilized DOR/MOR heteromer, shifted the ED(50) for analgesia back to the left. Taken together, these data suggest an anti-analgesic role for the DOR/MOR heteromer in pain. In conclusion, antagonists selective for DOR/MOR heteromer could provide an avenue for alleviating reduced analgesic response during chronic pain treatment. Public Library of Science 2013-03-15 /pmc/articles/PMC3598907/ /pubmed/23554887 http://dx.doi.org/10.1371/journal.pone.0058362 Text en © 2013 Milan-Lobo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Milan-Lobo, Laura
Enquist, Johan
van Rijn, Richard M.
Whistler, Jennifer L.
Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism
title Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism
title_full Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism
title_fullStr Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism
title_full_unstemmed Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism
title_short Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism
title_sort anti-analgesic effect of the mu/delta opioid receptor heteromer revealed by ligand-biased antagonism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598907/
https://www.ncbi.nlm.nih.gov/pubmed/23554887
http://dx.doi.org/10.1371/journal.pone.0058362
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