Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats. Mechanistically, tumor-associated production of vascular endothelial growth factor (VEGF) activated the receptor VEGFR2 on DRGs, which increased the abundance of the calcineurin inhibitor DSCR1, which, in turn, decreased calcineurin-mediated activation of the transcription factor NFAT, thereby reducing the transcription of the gene encoding TRESK. Intrathecal application of exogenous calcineurin to tumor-bearing rats rescued TRESK abundance and abrogated both DRG hyperexcitability and pain hypersensitivity, whereas either inhibition or knockdown of calcineurin in normal rats reduced TRESK abundance and increased DRG excitability and pain sensitivity. These findings identify a potentially targetable mechanism that may cause bone metastasis-associated pain in cancer patients.

中文翻译：

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感觉神经元中TRESK两孔结构域钾通道的减少减少是与骨转移相关的疼痛的基础。

癌症相关的疼痛使人衰弱。了解引起它的机制可以为药物开发提供信息，这可能会改善患者的生活质量。在这里，我们发现在背根神经节（DRG）神经元中称为TRESK的钾通道减少导致敏锐的伤害性感觉神经元和与癌症相关的疼痛。DRG神经元中过表达的TRESK抑制了骨转移模型大鼠的肿瘤诱导的神经元过度兴奋和疼痛超敏反应，而敲低TRESK则增加了正常大鼠中的神经元过度兴奋和疼痛超敏反应。从机制上讲，肿瘤相关的血管内皮生长因子（VEGF）的产生激活了DRGs上的受体VEGFR2，从而增加了钙调神经磷酸酶抑制剂DSCR1的丰度，进而使钙调磷酸酶抑制剂DSCR1富集。减少钙调神经磷酸酶介导的转录因子NFAT激活，从而减少编码TRESK的基因的转录。在荷瘤大鼠中鞘内施用钙调神经磷酸酶可以挽救TRESK的丰度，并消除DRG过度兴奋性和疼痛超敏性，而正常大鼠中钙调神经磷酸酶的抑制或抑制可降低TRESK的丰度并增加DRG兴奋性和疼痛敏感性。这些发现确定了可能导致癌症患者骨转移相关疼痛的潜在靶向机制。正常大鼠中钙调神经磷酸酶的抑制或抑制可降低TRESK的丰度并增加DRG的兴奋性和疼痛敏感性。这些发现确定了可能导致癌症患者骨转移相关疼痛的潜在靶向机制。正常大鼠中钙调神经磷酸酶的抑制或抑制可降低TRESK的丰度并增加DRG的兴奋性和疼痛敏感性。这些发现确定了可能导致癌症患者骨转移相关疼痛的潜在靶向机制。