Knock-In Mice with NOP-eGFP Receptors Identify Receptor Cellular and Regional Localization

Ozawa, Akihiko; Brunori, Gloria; Mercatelli, Daniela; Wu, Jinhua; Cippitelli, Andrea; Zou, Bende; Xie, Xinmin; Williams, Melissa; Zaveri, Nurulain T.; Low, Sarah; Scherrer, Grégory; Kieffer, Brigitte L.; Toll, Lawrence

doi:10.1523/jneurosci.5122-14.2015

Cited by 59 publications

(69 citation statements)

References 58 publications

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“…Recently, knock-in mice have been developed with NOP-eGFP receptors in place of the native receptor (Ozawa et al, 2015), similar to knock-in mice containing delta-eGFP and mu-mCherry receptors (Scherrer et al, 2006;Erbs et al, 2015). For each of these mutant mice, the tagged receptor has been valuable in identifying receptor location and trafficking without the need for problematic opioid receptor antibodies, with resolution far superior to in vitro autoradiography.…”

Section: B Location Of Nociceptin Opioid Peptide Receptorsmentioning

confidence: 99%

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Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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Section: B Location Of Nociceptin Opioid Peptide Receptorsmentioning

confidence: 99%

“…In this regard, new tools being currently developed will soon be available to study NOP receptor circuitry. NOP-eGFP knockin mice have already demonstrated utility in identifying NOP receptor-containing cells in the brain, spinal cord, and DRG (Ozawa et al, 2015).…”

Section: Future Directions and New Toolsmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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“…In particular, recent efforts using MOR-mCherry, and DOR-eGFP have determined that these receptors are expressed in distinct but overlapping populations dependent on the cell type and location. Furthermore, findings in NOPR-eGFP mice were recently published (91), and it was revealed that this receptor is expressed in a subpopulation of DRG neurons. Additionally, initial and intriguing data were reported on internalization properties of NOPR within endogenous neuronal cultures (91).…”

Section: Rodent Genetic Tools For Dissecting Opioid Receptor Functionmentioning

confidence: 90%

“…Furthermore, findings in NOPR-eGFP mice were recently published (91), and it was revealed that this receptor is expressed in a subpopulation of DRG neurons. Additionally, initial and intriguing data were reported on internalization properties of NOPR within endogenous neuronal cultures (91). These types of receptor-fusion fluorophore approaches do come with caveats, given that the GFP/mCherry tag could interfere with receptor trafficking and function.…”

Section: Rodent Genetic Tools For Dissecting Opioid Receptor Functionmentioning

confidence: 90%

“…Finally, targeted GFP-, YFP-, and mCherry-opioid-receptor fusion mice are now being used to examine endogenous receptor localization, trafficking, and expression (91) (92) (93). Due to the constraints and limitations of opioid receptor antibodies, these mice have proven useful in determining the localization and kinetics of receptors within specific neuronal cell types.…”

Section: Rodent Genetic Tools For Dissecting Opioid Receptor Functionmentioning

confidence: 99%

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New Technologies for Elucidating Opioid Receptor Function

Bruchas

Roth

2016

Trends in Pharmacological Sciences

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Recent advances in technology, including high resolution crystal structures of opioid receptors, novel chemical tools, and new genetic approaches have provided an unparalleled pallette of tools for deconstructing opioid receptor actions in vitro and in vivo. Here we provide a brief description of our understanding of opioid receptor function from both molecular and atomic perspectives, as well as their role in neural circuits in vivo. We then show how insights into the molecular details of opioid actions can facilitate the creation of functionally-selective (biased) and photoswitchable opioid ligands. Finally, we describe how newly engineered opioid receptor-based chemo- and optogenetic tools, and new mouse lines are expanding and transforming our understanding of opioid function and, perhaps, paving the way for new therapeutics.

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Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse

Kiguchi

Ding

2020

J of Neuroscience Research

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Following the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) as an endogenous ligand for the NOP receptor, ample evidence has revealed unique functional profiles of the N/OFQ-NOP receptor system. NOP receptors are expressed in key neural substrates involved in pain and reward modulation. In non-human primates (NHPs), NOP receptor activation effectively exerts antinociception and anti-hypersensitivity at the spinal and supraspinal levels. Moreover, NOP receptor activation inhibits dopaminergic transmission and synergistically enhances mu-opioid peptide (MOP) receptor-mediated analgesia. In this article, we discuss the functional profiles of ligands with dual NOP and MOP receptor agonist activities and highlight their optimal functional efficacy for pain relief and drug abuse treatment. Through coactivation of NOP and MOP receptors, bifunctional NOP/MOP receptor "partial" agonists (e.g., AT-121, BU08028, and BU10038) reveal a wider therapeutic window with fewer side effects. These newly developed ligands potently induce antinociception without MOP receptor agonist-associated side effects such as abuse potential, respiratory depression, itch sensation, and physical dependence. In addition, in both rodent and NHP models, bifunctional NOP/MOP receptor agonists can attenuate reward processing and/or the reinforcing effects of opioids and other abused drugs. While a mixed NOP/opioid receptor "full" agonist cebranopadol is undergoing clinical trials, bifunctional NOP/MOP "partial" agonists exhibit promising therapeutic profiles in translational NHP models for the treatment of pain and opioid abuse. This class of drugs demonstrates the therapeutic advantage of NOP and MOP receptor coactivation, indicating a greater potential for future development.

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Knock-In Mice with NOP-eGFP Receptors Identify Receptor Cellular and Regional Localization

Abstract: The nociceptin/orphanin FQ (NOP) receptor, the fourth member of the opioid receptor family, is involved in many processes common to the opioid receptors including pain and drug abuse.

Cited by 59 publications

References 58 publications

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

New Technologies for Elucidating Opioid Receptor Function

Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse

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