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Research ArticleArticle

Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor

Georgina L. Thompson, J. Robert Lane, Thomas Coudrat, Patrick M. Sexton, Arthur Christopoulos and Meritxell Canals
Molecular Pharmacology August 2015, 88 (2) 335-346; DOI: https://doi.org/10.1124/mol.115.098848
Georgina L. Thompson
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.)
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J. Robert Lane
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.)
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Thomas Coudrat
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.)
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Patrick M. Sexton
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.)
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Arthur Christopoulos
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.)
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Meritxell Canals
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.)
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Abstract

Biased agonism is having a major impact on modern drug discovery, and describes the ability of distinct G protein–coupled receptor (GPCR) ligands to activate different cell signaling pathways, and to result in different physiologic outcomes. To date, most studies of biased agonism have focused on synthetic molecules targeting various GPCRs; however, many of these receptors have multiple endogenous ligands, suggesting that “natural” bias may be an unappreciated feature of these GPCRs. The μ-opioid receptor (MOP) is activated by numerous endogenous opioid peptides, remains an attractive therapeutic target for the treatment of pain, and exhibits biased agonism in response to synthetic opiates. The aim of this study was to rigorously assess the potential for biased agonism in the actions of endogenous opioids at the MOP in a common cellular background, and compare these to the effects of the agonist d-Ala2-N-MePhe4-Gly-ol enkephalin (DAMGO). We investigated activation of G proteins, inhibition of cAMP production, extracellular signal-regulated kinase 1 and 2 phosphorylation, β-arrestin 1/2 recruitment, and MOP trafficking, and applied a novel analytical method to quantify biased agonism. Although many endogenous opioids displayed signaling profiles similar to that of DAMGO, α-neoendorphin, Met-enkephalin-Arg-Phe, and the putatively endogenous peptide endomorphin-1 displayed particularly distinct bias profiles. These may represent examples of natural bias if it can be shown that they have different signaling properties and physiologic effects in vivo compared with other endogenous opioids. Understanding how endogenous opioids control physiologic processes through biased agonism can reveal vital information required to enable the design of biased opioids with improved pharmacological profiles and treat diseases involving dysfunction of the endogenous opioid system.

Footnotes

    • Received March 4, 2015.
    • Accepted May 26, 2015.
  • M.C. is a Monash Fellow. A.C. and P.M.S. are Principal Research Fellows of the National Health and Medical Research Council (NHMRC) of Australia. J.R.L. is a Monash University Larkins Fellow and an RD Wright Biomedical Career Development Fellow (NHMRC). This work was funded in part by the NHMRC [Program Grant APP1055134 to A.C. and P.M.S.] and the Monash Institute of Pharmaceutical Sciences Large Grant Support Scheme (M.C.). G.L.T. scholarship was funded by the Australian Commonwealth Government Department of Defence.

  • dx.doi.org/10.1124/mol.115.098848.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (2)
Molecular Pharmacology
Vol. 88, Issue 2
1 Aug 2015
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Research ArticleArticle

Endogenous Biased Agonism at the μ-Opioid Receptor

Georgina L. Thompson, J. Robert Lane, Thomas Coudrat, Patrick M. Sexton, Arthur Christopoulos and Meritxell Canals
Molecular Pharmacology August 1, 2015, 88 (2) 335-346; DOI: https://doi.org/10.1124/mol.115.098848

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Research ArticleArticle

Endogenous Biased Agonism at the μ-Opioid Receptor

Georgina L. Thompson, J. Robert Lane, Thomas Coudrat, Patrick M. Sexton, Arthur Christopoulos and Meritxell Canals
Molecular Pharmacology August 1, 2015, 88 (2) 335-346; DOI: https://doi.org/10.1124/mol.115.098848
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