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Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels

  1. Sandeep Dembla
  2. Marc Behrendt
  3. Florian Mohr
  4. Christian Goecke
  5. Julia Sondermann
  6. Franziska M Schneider
  7. Marlene Schmidt
  8. Julia Stab
  9. Raissa Enzeroth
  10. Michael G Leitner
  11. Paulina Nuñez- Badinez
  12. Jochen Schwenk
  13. Bernd Nürnberg
  14. Alejandro Cohen
  15. Stephan E Philipp
  16. Wolfgang Greffrath
  17. Moritz Bünemann
  18. Dominik Oliver
  19. Eleonora Zakharian
  20. Manuela Schmidt
  21. Johannes Oberwinkler  Is a corresponding author
  1. Philipps-Universität Marburg, Germany
  2. Max-Planck-Institut für experimentelle Medizin, Germany
  3. Universität des Saarlandes, Germany
  4. Medical Faculty Mannheim of Heidelberg University, Germany
  5. University of Freiburg, Germany
  6. Universität Tübingen, Germany
  7. Dalhousie University, Canada
  8. Philipp University of Marburg, Germany
  9. University of Illinois College of Medicine, United States
Research Article
  • Cited 40
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Cite this article as: eLife 2017;6:e26280 doi: 10.7554/eLife.26280

Abstract

Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here we show in neurons of murine dorsal root ganglion cells that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1. Inhibition of TRPM3 channels occurs via a short signaling cascade involving Gβγ proteins, which form a complex with TRPM3. Accordingly, activation of peripheral µORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral µOR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy.

Article and author information

Author details

  1. Sandeep Dembla

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Marc Behrendt

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Florian Mohr

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Christian Goecke

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Julia Sondermann

    Max-Planck-Institut für experimentelle Medizin, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Franziska M Schneider

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Marlene Schmidt

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Julia Stab

    Experimentelle und klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Raissa Enzeroth

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Michael G Leitner

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Paulina Nuñez- Badinez

    Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Jochen Schwenk

    Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Bernd Nürnberg

    Abteilung für Pharmakologie und Experimentelle Therapie, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Tübingen, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Alejandro Cohen

    Proteomics and Mass Spectrometry Core Facility, Life Sciences Research Institute, Dalhousie University, Halifax, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. Stephan E Philipp

    Experimentelle und klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  16. Wolfgang Greffrath

    Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  17. Moritz Bünemann

    Institut für Pharmakologie und Klinische Pharmazie, Philipp University of Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  18. Dominik Oliver

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  19. Eleonora Zakharian

    Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Manuela Schmidt

    Max-Planck-Institut für experimentelle Medizin, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  21. Johannes Oberwinkler

    Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
    For correspondence
    johannes.oberwinkler@uni-marburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8541-3626

Funding

Deutsche Forschungsgemeinschaft (Emmy Noether Programm)

  • Manuela Schmidt

Deutsche Forschungsgemeinschaft (GK 1326)

  • Johannes Oberwinkler

Max-Planck-Gesellschaft (PhD fellowship)

  • Julia Sondermann

Philipps-Universität Marburg (MARA PhD fellowship)

  • Christian Goecke

Deutsche Forschungsgemeinschaft (SFB 593)

  • Johannes Oberwinkler

Deutsche Forschungsgemeinschaft (SFB 894)

  • Johannes Oberwinkler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experimentation was approved and carried out in strict compliance withinstitutional guidelines of the Max Planck Society and guidelines of the Landesamt fürVerbraucherschutz und Lebensmittelsicherheit of Lower Saxony, Germany (AZ 33.9-42502-04-14/1638)

Reviewing Editor

  1. Kenton J Swartz, National Institutes of Health, United States

Publication history

  1. Received: February 23, 2017
  2. Accepted: August 7, 2017
  3. Accepted Manuscript published: August 15, 2017 (version 1)
  4. Version of Record published: September 11, 2017 (version 2)

Copyright

© 2017, Dembla et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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    Transient receptor potential melastatin 3 (TRPM3) channels are activated by heat, and chemical ligands such as pregnenolone sulphate (PregS) and CIM0216. Here, we show that activation of receptors coupled to heterotrimeric Gi/o proteins inhibits TRPM3 channels. This inhibition was alleviated by co-expression of proteins that bind the βγ subunits of heterotrimeric G-proteins (Gβγ). Co-expression of Gβγ, but not constitutively active Gαi or Gαo, inhibited TRPM3 currents. TRPM3 co-immunoprecipitated with Gβ, and purified Gβγ proteins applied to excised inside-out patches inhibited TRPM3 currents, indicating a direct effect. Baclofen and somatostatin, agonists of Gi-coupled receptors, inhibited Ca2+ signals induced by PregS and CIM0216 in mouse dorsal root ganglion (DRG) neurons. The GABAB receptor agonist baclofen also inhibited inward currents induced by CIM0216 in DRG neurons, and nocifensive responses elicited by this TRPM3 agonist in mice. Our data uncover a novel signaling mechanism regulating TRPM3 channels.

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