Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model.
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 (TNFalpha) antagonist etanercept. In naive mice, exogenous TNFalpha evoked heat hyperalgesia in vivo and sensitized nociceptive nerve fibers to heat in vitro. TNFalpha 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 TNFalpha as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.
Constantin
Cristina E
CE
Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, 6020 Innsbruck, Austria.
Mair
Norbert
N
Sailer
Claudia A
CA
Andratsch
Manfred
M
Xu
Zhen-Zhong
ZZ
Blumer
Michael J F
MJ
Scherbakov
Nadja
N
Davis
John B
JB
Bluethmann
Horst
H
Ji
Ru-Rong
RR
Kress
Michaela
M
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002277:Carcinoma / Q000150:complications* / Q000378:metabolism*; D002478:Cells, Cultured; D000068800:Etanercept; D017353:Gene Deletion; D006614:Hindlimb; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D009475:Neurons, Afferent / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept; D002211:Capsaicin