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The Journal of Neuroscience, October 28, 2009, 29(43):13473-13483; doi:10.1523/JNEUROSCI.1822-09.2009

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Cellular/Molecular
A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

Manfred Andratsch,¹ Norbert Mair,¹ Cristina E. Constantin,¹ Nadja Scherbakov,¹ Camilla Benetti,¹ Serena Quarta,¹ Christian Vogl,¹ Claudia A. Sailer,¹ Nurcan Üceyler,² Johannes Brockhaus,³ Rudolf Martini,² Claudia Sommer,² Hanns Ulrich Zeilhofer,³ Werner Müller,⁴ Rohini Kuner,⁵ John B. Davis,⁶ Stefan Rose-John,⁷ and Michaela Kress¹

¹Department of Physiology and Medical Physics, Division of Physiology, Innsbruck Medical University, A-6020 Innsbruck, Austria, ²Department of Neurology, University of Würzburg, 97080 Würzburg, Germany, ³Institute of Pharmacology and Toxicology, University of Zürich, Switzerland and Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, 8057 Zürich, Switzerland, ⁴Faculty of Life Science, University of Manchester, M13 9PL Manchester, United Kingdom, ⁵Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany, ⁶Discovery Technology Group, Research and Development, GlaxoSmithKline, CM19 5AW Harlow, Essex, United Kingdom, and ⁷Institute of Biochemistry, Christian-Albrechts-University, D-24098 Kiel, Germany

Correspondence should be addressed to Dr. Michaela Kress, Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria. Email: michaela.kress{at}i-med.ac.at

Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity both in vitro and in vivo. This process was mediated by activation of PKC- via Gab1/2/PI₃K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lack gp130 specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.

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Received April 16, 2009; revised July 31, 2009; accepted Aug. 19, 2009.

Correspondence should be addressed to Dr. Michaela Kress, Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria. Email: michaela.kress{at}i-med.ac.at

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