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In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling

Interest has emerged in biased agonists at the mu opioid receptor (MOR) as a possible means for maintaining potent analgesis with reduced side effect profiles. While approaches measuring in vitro biased agonism are used in the development of these compounds, their therapeutic utility will ultimately...

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Autores principales: Zhang, Xiao, Hutchins, Shaurita D., Blough, Bruce E., Vallender, Eric J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312292/
https://www.ncbi.nlm.nih.gov/pubmed/32503269
http://dx.doi.org/10.3390/ijms21113999
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author Zhang, Xiao
Hutchins, Shaurita D.
Blough, Bruce E.
Vallender, Eric J.
author_facet Zhang, Xiao
Hutchins, Shaurita D.
Blough, Bruce E.
Vallender, Eric J.
author_sort Zhang, Xiao
collection PubMed
description Interest has emerged in biased agonists at the mu opioid receptor (MOR) as a possible means for maintaining potent analgesis with reduced side effect profiles. While approaches measuring in vitro biased agonism are used in the development of these compounds, their therapeutic utility will ultimately be determined by in vivo functional effects. Nonhuman primates (NHPs) are the most translational model for evaluating the behavioral effects of candidate medications, but biased signaling of these drugs at NHP MOR receptors has been unstudied. The goal of the current work was to characterize MOR ligand bias in rhesus macaques, focusing on agonists that have previously been reported to show different patterns of biased agonism in rodents and humans. Downstream signaling pathways that responded to MOR activation were identified using a luciferase reporter array. Concentration-response curves for specific pathways (cAMP, NF-ĸB, MAPK/JNK) were generated using six agonists previously reported to differ in terms of signaling bias at rodent and human MORs. Using DAMGO as a reference ligand, relative cAMP, NF-ĸB and MAPK/JNK signaling by morphine, endomorphin-1, and TRV130 were found to be comparable between species. Further, the bias patterns of across ligands for NF-ĸB and MAPK/JNK were largely similar between species. There was a high degree of concordance between rhesus macaque and human MOR receptor signaling bias for all agonists tested, further demonstrating their utility for future translational behavioral studies.
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spelling pubmed-73122922020-06-26 In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling Zhang, Xiao Hutchins, Shaurita D. Blough, Bruce E. Vallender, Eric J. Int J Mol Sci Article Interest has emerged in biased agonists at the mu opioid receptor (MOR) as a possible means for maintaining potent analgesis with reduced side effect profiles. While approaches measuring in vitro biased agonism are used in the development of these compounds, their therapeutic utility will ultimately be determined by in vivo functional effects. Nonhuman primates (NHPs) are the most translational model for evaluating the behavioral effects of candidate medications, but biased signaling of these drugs at NHP MOR receptors has been unstudied. The goal of the current work was to characterize MOR ligand bias in rhesus macaques, focusing on agonists that have previously been reported to show different patterns of biased agonism in rodents and humans. Downstream signaling pathways that responded to MOR activation were identified using a luciferase reporter array. Concentration-response curves for specific pathways (cAMP, NF-ĸB, MAPK/JNK) were generated using six agonists previously reported to differ in terms of signaling bias at rodent and human MORs. Using DAMGO as a reference ligand, relative cAMP, NF-ĸB and MAPK/JNK signaling by morphine, endomorphin-1, and TRV130 were found to be comparable between species. Further, the bias patterns of across ligands for NF-ĸB and MAPK/JNK were largely similar between species. There was a high degree of concordance between rhesus macaque and human MOR receptor signaling bias for all agonists tested, further demonstrating their utility for future translational behavioral studies. MDPI 2020-06-03 /pmc/articles/PMC7312292/ /pubmed/32503269 http://dx.doi.org/10.3390/ijms21113999 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Xiao
Hutchins, Shaurita D.
Blough, Bruce E.
Vallender, Eric J.
In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling
title In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling
title_full In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling
title_fullStr In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling
title_full_unstemmed In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling
title_short In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling
title_sort in vitro effects of ligand bias on primate mu opioid receptor downstream signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312292/
https://www.ncbi.nlm.nih.gov/pubmed/32503269
http://dx.doi.org/10.3390/ijms21113999
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