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Molecular Pharmacology

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Research ArticleArticle

Caged Naloxone Reveals Opioid Signaling Deactivation Kinetics

Matthew R. Banghart, John T. Williams, Ruchir C. Shah, Luke D. Lavis and Bernardo L. Sabatini
Molecular Pharmacology November 2013, 84 (5) 687-695; DOI: https://doi.org/10.1124/mol.113.088096
Matthew R. Banghart
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts (M.R.B., R.C.S., B.L.S.); Vollum Institute, Oregon Health & Science University, Portland, Oregon (J.T.W.); and Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia (L.D.L.)
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John T. Williams
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts (M.R.B., R.C.S., B.L.S.); Vollum Institute, Oregon Health & Science University, Portland, Oregon (J.T.W.); and Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia (L.D.L.)
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Ruchir C. Shah
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts (M.R.B., R.C.S., B.L.S.); Vollum Institute, Oregon Health & Science University, Portland, Oregon (J.T.W.); and Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia (L.D.L.)
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Luke D. Lavis
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts (M.R.B., R.C.S., B.L.S.); Vollum Institute, Oregon Health & Science University, Portland, Oregon (J.T.W.); and Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia (L.D.L.)
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Bernardo L. Sabatini
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts (M.R.B., R.C.S., B.L.S.); Vollum Institute, Oregon Health & Science University, Portland, Oregon (J.T.W.); and Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia (L.D.L.)
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Abstract

The spatiotemporal dynamics of opioid signaling in the brain remain poorly defined. Photoactivatable opioid ligands provide a means to quantitatively measure these dynamics and their underlying mechanisms in brain tissue. Although activation kinetics can be assessed using caged agonists, deactivation kinetics are obscured by slow clearance of agonist in tissue. To reveal deactivation kinetics of opioid signaling we developed a caged competitive antagonist that can be quickly photoreleased in sufficient concentrations to render agonist dissociation effectively irreversible. Carboxynitroveratryl-naloxone (CNV-NLX), a caged analog of the competitive opioid antagonist NLX, was readily synthesized from commercially available NLX in good yield and found to be devoid of antagonist activity at heterologously expressed opioid receptors. Photolysis in slices of rat locus coeruleus produced a rapid inhibition of the ionic currents evoked by multiple agonists of the μ-opioid receptor (MOR), but not of α-adrenergic receptors, which activate the same pool of ion channels. Using the high-affinity peptide agonist dermorphin, we established conditions under which light-driven deactivation rates are independent of agonist concentration and thus intrinsic to the agonist-receptor complex. Under these conditions, some MOR agonists yielded deactivation rates that are limited by G protein signaling, whereas others appeared limited by agonist dissociation. Therefore, the choice of agonist determines which feature of receptor signaling is unmasked by CNV-NLX photolysis.

Footnotes

    • Received June 22, 2013.
    • Accepted August 19, 2013.
  • This work was supported by the Howard Hughes Medical Institute (to B.L.S. and L.D.L.); the National Institutes of Health National Institute of Mental Health [Grant MH085498] (to B.L.S.); and the National Institutes of Health National Institute on Drug Abuse [Grant DA08163] (to J.T.W.) and [Grant DA034648] (to M.R.B.); and postdoctoral fellowships from the Helen Hay Whitney Foundation and the Charles A. King Trust, N.A., Bank of America, Co-Trustee (to M.R.B.).

  • dx.doi.org/10.1124/mol.113.088096.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (5)
Molecular Pharmacology
Vol. 84, Issue 5
1 Nov 2013
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Research ArticleArticle

Light-Triggered Opioid Antagonism

Matthew R. Banghart, John T. Williams, Ruchir C. Shah, Luke D. Lavis and Bernardo L. Sabatini
Molecular Pharmacology November 1, 2013, 84 (5) 687-695; DOI: https://doi.org/10.1124/mol.113.088096

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Research ArticleArticle

Light-Triggered Opioid Antagonism

Matthew R. Banghart, John T. Williams, Ruchir C. Shah, Luke D. Lavis and Bernardo L. Sabatini
Molecular Pharmacology November 1, 2013, 84 (5) 687-695; DOI: https://doi.org/10.1124/mol.113.088096
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