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

Sandeep Dembla; Marc Behrendt; Florian Mohr; Christian Goecke; Julia Sondermann; Franziska M. Schneider; Marlene Schmidt; Julia Stab; Raissa Enzeroth; Michael G. Leitner; Paulina Nuñez-Badinez; Jochen Schwenk; Bernd Nürnberg; Alejandro Cohen; Stephan E. Philipp; Wolfgang Greffrath; Moritz Bünemann; Dominik Oliver; Eleonora Zakharian; Manuela Schmidt; Johannes Oberwinkler

doi:10.7554/eLife.26280

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

Sandeep Dembla, Marc Behrendt, Florian Mohr, Christian Goecke, Julia Sondermann, Franziska M. Schneider, Marlene Schmidt, Julia Stab, Raissa Enzeroth, Michael G. Leitner, Paulina Nuñez-Badinez, Jochen Schwenk, Bernd Nürnberg, Alejandro Cohen, Stephan E. Philipp, Wolfgang Greffrath, Moritz Bünemann, Dominik Oliver, Eleonora Zakharian, Manuela SchmidtJohannes Oberwinkler

Medicine

Résultat de recherche: Article › examen par les pairs

91 Citations (Scopus)

Résumé

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 ganglia 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.

Langue d'origine	English
Numéro d'article	e26280
Journal	eLife
Volume	6
DOI	https://doi.org/10.7554/eLife.26280
Statut de publication	Published - août 15 2017

Note bibliographique

Funding Information:
1Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany; 2Max-Planck-Institut für Experimentelle Medizin, Göttingen, Germany; 3Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany; 4Department of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany; 5Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 6Abteilung für Pharmakologie und Experimentelle Therapie, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Tübingen, Tübingen, Germany; 7Proteomics and Mass Spectrometry Core Facility, Life Sciences Research Institute, Dalhousie University, Halifax, Nova Scotia, Canada; 8Institut für Pharmakologie und Klinische Pharmazie, Philipps-Universität Marburg, Marburg, Germany; 9Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, United States

Publisher Copyright:
© Dembla et al.

ASJC Scopus Subject Areas

General Neuroscience
General Biochemistry,Genetics and Molecular Biology
General Immunology and Microbiology

Accès au document

10.7554/eLife.26280

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Dembla, S., Behrendt, M., Mohr, F., Goecke, C., Sondermann, J., Schneider, F. M., Schmidt, M., Stab, J., Enzeroth, R., Leitner, M. G., Nuñez-Badinez, P., Schwenk, J., Nürnberg, B., Cohen, A., Philipp, S. E., Greffrath, W., Bünemann, M., Oliver, D., Zakharian, E., ... Oberwinkler, J. (2017). Anti-nociceptive action of peripheral mu- opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels. eLife, 6, Article e26280. https://doi.org/10.7554/eLife.26280

Dembla, S, Behrendt, M, Mohr, F, Goecke, C, Sondermann, J, Schneider, FM, Schmidt, M, Stab, J, Enzeroth, R, Leitner, MG, Nuñez-Badinez, P, Schwenk, J, Nürnberg, B, Cohen, A, Philipp, SE, Greffrath, W, Bünemann, M, Oliver, D, Zakharian, E, Schmidt, M & Oberwinkler, J 2017, 'Anti-nociceptive action of peripheral mu- opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels', eLife, vol. 6, e26280. https://doi.org/10.7554/eLife.26280

@article{49add415bec447a1abc159ed13341fcb,

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

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 ganglia 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.",

author = "Sandeep Dembla and Marc Behrendt and Florian Mohr and Christian Goecke and Julia Sondermann and Schneider, {Franziska M.} and Marlene Schmidt and Julia Stab and Raissa Enzeroth and Leitner, {Michael G.} and Paulina Nu{\~n}ez-Badinez and Jochen Schwenk and Bernd N{\"u}rnberg and Alejandro Cohen and Philipp, {Stephan E.} and Wolfgang Greffrath and Moritz B{\"u}nemann and Dominik Oliver and Eleonora Zakharian and Manuela Schmidt and Johannes Oberwinkler",

note = "Funding Information: 1Institut f{\"u}r Physiologie und Pathophysiologie, Philipps-Universit{\"a}t Marburg, Marburg, Germany; 2Max-Planck-Institut f{\"u}r Experimentelle Medizin, G{\"o}ttingen, Germany; 3Experimentelle und Klinische Pharmakologie und Toxikologie, Universit{\"a}t des Saarlandes, Homburg, Germany; 4Department of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany; 5Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 6Abteilung f{\"u}r Pharmakologie und Experimentelle Therapie, Institut f{\"u}r Experimentelle und Klinische Pharmakologie und Toxikologie, Universit{\"a}t T{\"u}bingen, T{\"u}bingen, Germany; 7Proteomics and Mass Spectrometry Core Facility, Life Sciences Research Institute, Dalhousie University, Halifax, Nova Scotia, Canada; 8Institut f{\"u}r Pharmakologie und Klinische Pharmazie, Philipps-Universit{\"a}t Marburg, Marburg, Germany; 9Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, United States Publisher Copyright: {\textcopyright} Dembla et al.",

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day = "15",

doi = "10.7554/eLife.26280",

language = "English",

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journal = "eLife",

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T1 - Anti-nociceptive action of peripheral mu- opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels

AU - Dembla, Sandeep

AU - Behrendt, Marc

AU - Mohr, Florian

AU - Goecke, Christian

AU - Sondermann, Julia

AU - Schneider, Franziska M.

AU - Schmidt, Marlene

AU - Stab, Julia

AU - Enzeroth, Raissa

AU - Leitner, Michael G.

AU - Nuñez-Badinez, Paulina

AU - Schwenk, Jochen

AU - Nürnberg, Bernd

AU - Cohen, Alejandro

AU - Philipp, Stephan E.

AU - Greffrath, Wolfgang

AU - Bünemann, Moritz

AU - Oliver, Dominik

AU - Zakharian, Eleonora

AU - Schmidt, Manuela

AU - Oberwinkler, Johannes

N1 - Funding Information: 1Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany; 2Max-Planck-Institut für Experimentelle Medizin, Göttingen, Germany; 3Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany; 4Department of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany; 5Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 6Abteilung für Pharmakologie und Experimentelle Therapie, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Tübingen, Tübingen, Germany; 7Proteomics and Mass Spectrometry Core Facility, Life Sciences Research Institute, Dalhousie University, Halifax, Nova Scotia, Canada; 8Institut für Pharmakologie und Klinische Pharmazie, Philipps-Universität Marburg, Marburg, Germany; 9Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, United States Publisher Copyright: © Dembla et al.

PY - 2017/8/15

Y1 - 2017/8/15

N2 - 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 ganglia 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.

AB - 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 ganglia 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.

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

Résumé

Note bibliographique

ASJC Scopus Subject Areas

Accès au document

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