TY - JOUR T1 - Endogenous Tumor Necrosis Factor α (TNFα) Requires TNF Receptor Type 2 to Generate Heat Hyperalgesia in a Mouse Cancer Model JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5072 LP - 5081 DO - 10.1523/JNEUROSCI.4476-07.2008 VL - 28 IS - 19 AU - Cristina E. Constantin AU - Norbert Mair AU - Claudia A. Sailer AU - Manfred Andratsch AU - Zhen-Zhong Xu AU - Michael J. F. Blumer AU - Nadja Scherbakov AU - John B. Davis AU - Horst Bluethmann AU - Ru-Rong Ji AU - Michaela Kress Y1 - 2008/05/07 UR - http://www.jneurosci.org/content/28/19/5072.abstract N2 - 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 α (TNFα) antagonist etanercept. In naive mice, exogenous TNFα evoked heat hyperalgesia in vivo and sensitized nociceptive nerve fibers to heat in vitro. TNFα 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 TNFα as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2. ER -