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The Journal of Neuroscience, May 7, 2008, 28(19):5072-5081; doi:10.1523/JNEUROSCI.4476-07.2008

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Cellular/Molecular
Endogenous Tumor Necrosis Factor {alpha} (TNF{alpha}) Requires TNF Receptor Type 2 to Generate Heat Hyperalgesia in a Mouse Cancer Model

Cristina E. Constantin,1 Norbert Mair,1 Claudia A. Sailer,1 Manfred Andratsch,1 Zhen-Zhong Xu,3 Michael J. F. Blumer,2 Nadja Scherbakov,1 John B. Davis,4 Horst Bluethmann,5 Ru-Rong Ji,3 and Michaela Kress1

1Division of Physiology, Department of Physiology and Medical Physics and 2Division of Clinical and Functional Anatomy, Innsbruck Medical University, 6020 Innsbruck, Austria, 3Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, 4Discovery Technology Group, Research and Development, GlaxoSmithKline, Harlow, Essex CM19 5AW, United Kingdom, and 5Roche Center for Medical Genomics, 4070 Basel, Switzerland

Correspondence should be addressed to Prof. 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

To provide a tool to investigate the mechanisms inducing and maintaining cancer-related pain and hyperalgesia, a soft tissue tumor/metastasis model was developed that is applicable in C57BL/6J wild-type and transgenic mice. We show that the experimental tumor-induced heat hyperalgesia and nociceptor sensitization were prevented by systemic treatment with the tumor necrosis factor {alpha} (TNF{alpha}) antagonist etanercept. In naive mice, exogenous TNF{alpha} evoked heat hyperalgesia in vivo and sensitized nociceptive nerve fibers to heat in vitro. TNF{alpha} enhanced the expression of the nociceptor-specific heat transducer ion channel transient receptor potential vanilloid 1 (TRPV1) and increased the amplitudes of capsaicin and heat-activated ionic currents via p38/MAP (mitogen-activated protein) kinase and PKC (protein kinase C). Deletion of the tumor necrosis factor receptor type 2 (TNFR2) gene attenuated heat hyperalgesia and prevented TRPV1 upregulation in tumor-bearing mice, whereas TNFR1 gene deletion played a minor role. We propose endogenous TNF{alpha} as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.

Key words: cancer-induced pain; heat hyperalgesia; primary afferent neurons; TNF{alpha}; TNF receptor type 2; TRPV1

Received Oct. 1, 2007; revised Feb. 27, 2008; accepted April 2, 2008.

Correspondence should be addressed to Prof. 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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