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
Affiliations
Sandeep Dembla
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Marc Behrendt
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Florian Mohr
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Christian Goecke
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Julia Sondermann
Max-Planck-Institut für Experimentelle Medizin, Göttingen, Germany
Franziska M Schneider
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Marlene Schmidt
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Julia Stab
Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany
Raissa Enzeroth
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Michael G Leitner
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Paulina Nuñez-Badinez
Department of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany
Jochen Schwenk
Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Bernd Nürnberg
Abteilung für Pharmakologie und Experimentelle Therapie, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Tübingen, Tübingen, Germany
Alejandro Cohen
Proteomics and Mass Spectrometry Core Facility, Life Sciences Research Institute, Dalhousie University, Halifax, Nova Scotia, Canada
Stephan E Philipp
Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany
Wolfgang Greffrath
Department of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany
Moritz Bünemann
Institut für Pharmakologie und Klinische Pharmazie, Philipps-Universität Marburg, Marburg, Germany
Dominik Oliver
Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany
Eleonora Zakharian
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, United States
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.
