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

• DOI: 10.1523/jneurosci.1822-09.2009
• Publication Date: 2009-10-28T18:05:25Z
• Authors: Manfred Andratsch; Norbert Mair; Cristina E. Const...; Nadja Scherbakov; Camilla Benetti; Serena Quarta; Christian Vogl; Claudia A. Sailer; Nurcan Üceyler; Johannes Brockhaus; Rudolf Martini; Claudia Sommer; Hanns Ulrich Zeil...; Werner Müller; Rohini Kuner; John B. Davis; Stefan Rose-John; Michaela Kress
• Keywords: Pain Threshold; 0301 basic medicine; Hot Temperature; Lung Neoplasms; Sensory Receptor Cells; 10050 Institute of Pharmacology and Toxicology; Pain; 610 Medicine & health; In Vitro Techniques; Mice; 03 medical and health sciences; Ganglia, Spinal; Cytokine Receptor gp130; Animals; Peripheral Nerves; Cells, Cultured; Mice, Knockout; Interleukin-6; Carcinoma; 2800 General Neuroscience; Nociceptors; 3. Good health; Mice, Inbred C57BL; Spinal Cord; 570 Life sciences; biology; Neoplasm Transplantation; Signal Transduction

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 bothin vitroandin vivo. This process was mediated by activation of PKC-δ 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 lackgp130specifically 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.