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

Author:

Dembla Sandeep1,Behrendt Marc1,Mohr Florian1,Goecke Christian1,Sondermann Julia2,Schneider Franziska M1,Schmidt Marlene1,Stab Julia3,Enzeroth Raissa1,Leitner Michael G1,Nuñez-Badinez Paulina4,Schwenk Jochen5,Nürnberg Bernd6,Cohen Alejandro7,Philipp Stephan E3,Greffrath Wolfgang4,Bünemann Moritz8,Oliver Dominik1,Zakharian Eleonora9,Schmidt Manuela2ORCID,Oberwinkler Johannes1ORCID

Affiliation:

1. Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany

2. Max-Planck-Institut für Experimentelle Medizin, Göttingen, Germany

3. Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany

4. Department of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany

5. Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

6. Abteilung für Pharmakologie und Experimentelle Therapie, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Tübingen, Tübingen, Germany

7. Proteomics and Mass Spectrometry Core Facility, Life Sciences Research Institute, Dalhousie University, Halifax, Nova Scotia, Canada

8. Institut für Pharmakologie und Klinische Pharmazie, Philipps-Universität Marburg, Marburg, Germany

9. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, United States

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.

Funder

Deutsche Forschungsgemeinschaft

Max-Planck-Gesellschaft

Philipps-Universität Marburg

Publisher

eLife Sciences Publications, Ltd

Subject

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

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