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Int. J. Mol. Sci. 2018, 19(1), 272; https://doi.org/10.3390/ijms19010272

Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?

1
Department of Physiology, Michigan State University, 567 Wilson Road, Room 2201 Biomedical and Physical Sciences Building, East Lansing, MI 48824, USA
2
Centre for Structural Systems Biology (CSSB), Notkestraße 85, 22607 Hamburg, Germany
3
Forschungszentrum Juelich GmbH, ICS-6, 52425 Juelich, Germany
*
Author to whom correspondence should be addressed.
Received: 8 December 2017 / Revised: 10 January 2018 / Accepted: 13 January 2018 / Published: 17 January 2018
(This article belongs to the Section Bioactives and Nutraceuticals)

Abstract

Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists. View Full-Text
Keywords: biased opioids; morphine; methionine-enkephalin; epinephrine; norepinephrine; enhancement; synergy; allosteric; mu opioid receptor; receptor dimers; dimerization biased opioids; morphine; methionine-enkephalin; epinephrine; norepinephrine; enhancement; synergy; allosteric; mu opioid receptor; receptor dimers; dimerization
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Root-Bernstein, R.; Turke, M.; Subhramanyam, U.K.T.; Churchill, B.; Labahn, J. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”? Int. J. Mol. Sci. 2018, 19, 272.

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