Endogenous tumor necrosis factor α(TNFα) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model
Endogenous tumor necrosis factor α(TNFα) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model
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DOI：
10.1523/jneurosci.4476-07.2008
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发表时间：
2008-05-07
影响因子：
5.3
通讯作者：
Kress, Michaela
中科院分区：
文献类型：
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作者：
Constantin, Cristina E.;Mair, Norbert;Kress, Michaela
为了提供研究诱导和维持癌症相关疼痛和痛觉过敏的机制的工具，开发了适用于C57 BL/6 J野生型和转基因小鼠的软组织肿瘤/转移模型。我们表明，实验性肿瘤诱导的热痛觉过敏和伤害感受器敏化预防全身治疗肿瘤坏死因子α（TNF α）拮抗剂依那西普。在幼稚小鼠中，外源性TNF α在体内诱发热痛觉过敏，并在体外使伤害性神经纤维对热敏感。TNF α增强伤害感受器特异性热传导离子通道瞬时受体电位香草酸1（TRPV 1）的表达，并通过p38/MAP（促分裂原活化蛋白）激酶和PKC（蛋白激酶C）增加辣椒素和热激活离子电流的幅度。肿瘤坏死因子受体2型（TNFR 2）基因的缺失减弱了热痛觉过敏，并阻止了TRPV 1在荷瘤小鼠中的上调，而TNFR 1基因缺失起着次要作用。我们认为内源性TNF α在癌症相关的热痛觉过敏和伤害感受器敏化中起关键作用，通过TNFR 2产生TRPV 1上调和敏化。
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 endogenousTNF alpha as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.