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

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.

Download Full-text

Dilemma of Addiction and Respiratory Depression in the Treatment of Pain: A Prototypical Endomorphin as a New Approach

Pain Medicine ◽

10.1093/pm/pnz122 ◽

2019 ◽

Vol 21 (5) ◽

pp. 992-1004 ◽

Cited By ~ 2

Author(s):

Lynn Webster ◽

William K Schmidt

Keyword(s):

Side Effects ◽

Respiratory Depression ◽

Opioid Receptor ◽

Severe Pain ◽

Mu Opioid Receptor ◽

Endogenous Opioid Peptides ◽

Endogenous Opioid ◽

Mu Opioid ◽

Receptor Agonists ◽

Opioid Receptor Agonists

Abstract Objective Although mu-opioid receptor agonists have been the mainstay of analgesic regimens for moderate to severe pain, they are associated with serious side effects, risks, and limitations. We evaluate the most serious risks associated with conventional opioids and compare these with the pharmacology of CYT-1010, a prototypical endomorphin and mu-opioid receptor agonist. Results Addiction and respiratory depression are serious risks of traditional mu-opioid analgesics. Mitigation strategies have been inadequate at addressing the opioid crisis and may interfere with the effective treatment of pain. Improved understanding of mu-opioid receptor biology and the discovery in 1997 of an additional and unique family of endogenous opioid peptides (endomorphins) have provided a pathway for dissociating analgesia from opioid-related adverse events and developing new classes of mu-opioid receptor agonists that use biased signaling and/or target novel sites to produce analgesia with reduced side effect liability. Endomorphin-1 and -2 are endogenous opioid peptides highly selective for mu-opioid receptors that exhibit potent analgesia with reduced side effects. CYT-1010 is a cyclized, D-lysine-containing analog of endomorphin-1 with a novel mechanism of action targeting traditional mu- and exon 11/truncated mu-opioid receptor 6TM variants. CYT-1010 preclinical data have demonstrated reduced abuse potential and analgesic potency exceeding that of morphine. In an initial phase 1 clinical study, CYT-1010 demonstrated significant analgesia vs baseline and no respiratory depression at the dose levels tested. Conclusions CYT-1010 and other novel mu-opioid receptor agonists in clinical development are promising alternatives to conventional opioids that may offer the possibility of safer treatment of moderate to severe pain.

Download Full-text

Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants

International Journal of Molecular Sciences ◽

10.3390/ijms22073779 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3779

Author(s):

Anna Abrimian ◽

Tamar Kraft ◽

Ying-Xian Pan

Keyword(s):

Opioid Receptor ◽

Opioid Peptides ◽

Splice Variants ◽

Mu Opioid Receptor ◽

Kappa Opioid Receptor ◽

Endogenous Opioid Peptides ◽

Endogenous Opioid ◽

Mu Opioid ◽

Protein Activation ◽

Biased Signaling

There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. The MOR gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, generating multiple splice variants or isoforms. One type of these splice variants, the full-length 7 transmembrane (TM) Carboxyl (C)-terminal variants, has the same receptor structures but contains different intracellular C-terminal tails. The pharmacological functions of several endogenous opioid peptides through the mouse, rat and human OPRM1 7TM C-terminal variants have been considerably investigated together with various mu opioid ligands. The current review focuses on the studies of these endogenous opioid peptides and summarizes the results from early pharmacological studies, including receptor binding affinity and G protein activation, and recent studies of β-arrestin2 recruitment and biased signaling, aiming to provide new insights into the mechanisms and functions of endogenous opioid peptides, which are mediated through the OPRM1 7TM C-terminal splice variants.

Download Full-text

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1115231108 ◽

2011 ◽

Vol 108 (49) ◽

pp. 19778-19783 ◽

Cited By ~ 89

Author(s):

S. Majumdar ◽

S. Grinnell ◽

V. Le Rouzic ◽

M. Burgman ◽

L. Polikar ◽

...

Keyword(s):

Side Effects ◽

G Protein ◽

Opioid Receptor ◽

Splice Variants ◽

Opioid Analgesics ◽

Mu Opioid Receptor ◽

Mu Opioid ◽

G Protein Coupled

Download Full-text

G protein signaling–biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2102178118 ◽

2021 ◽

Vol 118 (48) ◽

pp. e2102178118

Author(s):

Edward L. Stahl ◽

Cullen L. Schmid ◽

Agnes Acevedo-Canabal ◽

Cai Read ◽

Travis W. Grim ◽

...

Keyword(s):

Signaling Pathway ◽

G Protein ◽

Opioid Receptor ◽

Mu Opioid Receptor ◽

G Protein Signaling ◽

Protein Signaling ◽

Mu Opioid ◽

Biased Agonism ◽

Gpcr Activation

The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor, which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein–biased mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR in a wash-resistant yet antagonist-reversible G protein–signaling state. Furthermore, we demonstrate that these structurally related biased agonists are noncompetitive for radiolabeled MOR antagonist binding, and while they stimulate G protein signaling in mouse brains, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long-lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.

Download Full-text

Region Specificity in Endogenous Opioid Peptides and Mu-opioid Receptor Gene Expression in Rat Brain Areas Involved in Addiction After Frequent Morphine Treatment

Jentashapir Journal of Cellular and Molecular Biology ◽

10.5812/jjcmb.121808 ◽

2022 ◽

Vol 12 (4) ◽

Author(s):

Shamseddin Ahmadi ◽

Kayvan Masoudi ◽

Shiva Mohammadi Talvar ◽

Mohammad Zobeiri ◽

Amir Khanizad ◽

...

Keyword(s):

Gene Expression ◽

Opioid Peptides ◽

Mu Opioid Receptor ◽

Morphine Treatment ◽

Endogenous Opioid Peptides ◽

Gene Expressions ◽

Endogenous Opioid ◽

Brain Areas ◽

Oprm1 Gene ◽

Mu Opioid

Backgrounds: Molecular mechanisms involved in adverse effects of morphine, including tolerance and dependence, have remained elusive. We examined possible alterations in the gene expression of proenkephalin (Penk), prodynorphin (Pdyn), and mu-opioid receptor (Oprm1) in reward brain areas following frequent morphine treatment. Methods: Two groups of male Wistar rats were used. The groups received either saline (1 mL/kg) or morphine (10 mg/kg) twice daily for eight days. On day 8, rats were decapitated, brain areas involved in addiction were dissected, including the midbrain, striatum, prefrontal cortex (PFC), hippocampus, and hypothalamus, and gene expression was evaluated with real-time PCR. Results: Prolonged morphine treatment decreased Penk, Pdyn, and Oprm1 gene expressions in the midbrain but upregulated them in the striatum compared to the control group treated with saline. Significant increases in Pdyn and Oprm1 gene expressions were detected in the PFC, but there was no significant difference in Penk gene expression between the two groups. Besides, Pdyn gene expression was decreased in the hippocampus and hypothalamus; however, no significant differences in Penk and Oprm1 gene expressions were detected between the groups in these areas. Conclusions: The expression of endogenous opioid peptides and receptors after frequent use of morphine follows a region specificity in brain areas involved in addiction. These alterations may result in new physiological setpoints outside the normal range, which need to be considered when using morphine in medicine.

Download Full-text

Heteromerization of endogenous mu and delta opioid receptors tunes mu opioid receptor signaling and trafficking

10.1101/455147 ◽

2018 ◽

Author(s):

Lyes Derouiche ◽

Muzeyyen Ugur ◽

Florian Pierre ◽

Anika Mann ◽

Stéphane Doridot ◽

...

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Mu Opioid Receptor ◽

Endogenous Opioid ◽

Endogenous Opioid Peptide ◽

Mu Opioid ◽

Nociceptive Transmission ◽

Delta Opioid Receptors ◽

The Impact

AbstractIncreasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures and in vivo. We established ligand selective mu-delta co-internalization upon activation by exogenous ligands and provide evidence for mu-delta co-internalization by the endogenous opioid peptide met-enkephalin, but not β-endorphin. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors and led to sorting to the lysosomal compartment. This alteration in the mu opioid receptor intracellular fate was accompanied by sustained ERK1/2 phosphorylation. In addition, increased mu-delta neuronal co-localization in the rostral ventromedial medulla in a chronic neuropathic state suggests that mu-delta heteromers are involved in the regulation of nociceptive transmission

Download Full-text