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Review ArticleReview Article

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

Lawrence Toll, Michael R. Bruchas, Girolamo Calo', Brian M. Cox and Nurulain T. Zaveri
Macdonald J. Christie, ASSOCIATE EDITOR
Pharmacological Reviews April 2016, 68 (2) 419-457; DOI: https://doi.org/10.1124/pr.114.009209
Lawrence Toll
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
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Michael R. Bruchas
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
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Girolamo Calo'
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
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Brian M. Cox
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
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Nurulain T. Zaveri
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
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Macdonald J. Christie
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
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Abstract

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.

Footnotes

  • This work was supported by National Institutes of Health National Institute of Drug Abuse [Grant R01DA023281] (L.T.), Grant R21DA034929 (M.R.B.), Grants R01DA014026 and R01DA027811 (N.T.Z.)] and by the FAR grant of the University of Ferrara (G.C.).

  • dx.doi.org/10.1124/pr.114.009209

  • U.S. Government work not protected by U.S. copyright
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Pharmacological Reviews: 68 (2)
Pharmacological Reviews
Vol. 68, Issue 2
1 Apr 2016
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Review ArticleReview Article

NOP Receptor Biology and Function

Lawrence Toll, Michael R. Bruchas, Girolamo Calo', Brian M. Cox and Nurulain T. Zaveri
Pharmacological Reviews April 1, 2016, 68 (2) 419-457; DOI: https://doi.org/10.1124/pr.114.009209

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Review ArticleReview Article

NOP Receptor Biology and Function

Lawrence Toll, Michael R. Bruchas, Girolamo Calo', Brian M. Cox and Nurulain T. Zaveri
Pharmacological Reviews April 1, 2016, 68 (2) 419-457; DOI: https://doi.org/10.1124/pr.114.009209
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  • Article
    • Abstract
    • I. Introduction
    • II. Nociceptin Opioid Peptide Receptor
    • III. Signal Transduction Pathways Activated by NOP Receptor Ligands
    • IV. Cellular Actions of Nociceptin Opioid Peptide Receptors
    • V. Biologic Actions of Nociceptin Opioid Peptide Receptors
    • VI. Nociceptin Opioid Peptide Receptor Ligands
    • VII. Future Directions and New Tools
    • VIII. Concludng Remarks
    • Disclosures
    • Authorship Contributions.
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