Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating multiple splice variants or isoforms via a variety of alternative splicing events. These OPRM1 splice variants can be categorized into three major types based on the receptor structure: (1) full-length 7 transmembrane (TM) C-terminal variants; (2) truncated 6TM; and (3) single TM variants. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating the distinct actions of various mu opioids. More importantly, the OPRM1 variants can be targeted for development of novel opioid analgesics that are potent against multiple types of pain, but devoid of many side-effects associated with traditional opiates. In this review, we provide an overview of OPRM1 alternative splicing and its functional relevance in opioid pharmacology.

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Expression of EGFP-amino-tagged human mu opioid receptor in Drosophila Schneider 2 cells: a potential expression system for large-scale production of G-protein coupled receptors

Protein Expression and Purification ◽

10.1016/s1046-5928(03)00140-2 ◽

2003 ◽

Vol 31 (1) ◽

pp. 123-132 ◽

Cited By ~ 37

Author(s):

Bénédicte G Perret ◽

Renaud Wagner ◽

Sandra Lecat ◽

Karl Brillet ◽

Gwénaël Rabut ◽

...

Keyword(s):

G Protein ◽

Opioid Receptor ◽

Large Scale ◽

Expression System ◽

Mu Opioid Receptor ◽

G Protein Coupled Receptors ◽

Scale Production ◽

Mu Opioid ◽

Large Scale Production ◽

G Protein Coupled

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Measuring ligand efficacy at the mu-opioid receptor using a conformational biosensor

eLife ◽

10.7554/elife.32499 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 11

Author(s):

Kathryn E Livingston ◽

Jacob P Mahoney ◽

Aashish Manglik ◽

Roger K Sunahara ◽

John R Traynor

Keyword(s):

G Protein ◽

Opioid Receptor ◽

Mu Opioid Receptor ◽

G Protein Coupled Receptors ◽

Physiological Effects ◽

Allosteric Modulators ◽

Mu Opioid ◽

Class A ◽

Orthosteric Ligands ◽

G Protein Coupled

The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (µ-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to µ-OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of µ-OR. We further show that positive allosteric modulators of µ-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell-free, signal transduction-independent and is generally applicable to GPCRs.

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Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2000017118 ◽

2021 ◽

Vol 118 (16) ◽

pp. e2000017118

Author(s):

Ram Kandasamy ◽

Todd M. Hillhouse ◽

Kathryn E. Livingston ◽

Kelsey E. Kochan ◽

Claire Meurice ◽

...

Keyword(s):

Side Effects ◽

G Protein ◽

Opioid Receptor ◽

Opioid Peptides ◽

Chinese Hamster ◽

Mu Opioid Receptor ◽

Endogenous Opioid Peptides ◽

Endogenous Opioid ◽

Mu Opioid

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

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Sending out Biased Signals: an Appropriate Proposition for Pain?

Douleur et Analgésie ◽

10.3166/dea-2019-0065 ◽

2019 ◽

Vol 32 (2) ◽

pp. 108-110 ◽

Cited By ~ 1

Author(s):

E. Besserer-Offroy ◽

P. Sarret

Keyword(s):

Side Effects ◽

Acute Pain ◽

Gold Standard ◽

Pain Treatment ◽

Opioid Analgesics ◽

Mu Opioid Receptor ◽

Clinical Development ◽

Mu Opioid ◽

Development Stages ◽

The Past

In the past few years, several biased ligands acting at the mu-opioid receptor were reported in the literature. These agonists are aimed at reducing pain while having fewer side effects than morphine, the gold standard of opioid analgesics. In this mini-review, we describe and discuss the recent advances in mu-biased ligands actually in preclinical and clinical development stages, including the latest U.S. Food and Drug Administration review of oliceridine, a biased mu-agonist for moderate to severe acute pain treatment developed by the company Trevena.

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