神经钙蛋白作为治疗癌性骨痛新靶点的研究

神经钙蛋白是参与胞内胞核感觉信号传递通路的蛋白，其最主要的下游调控作用因子是NFAT。最近的研究发现NFAT在大鼠神经病理性疼痛中表达上调，抑制NFAT上调能够有效减轻其机械性异常疼痛，提示NFAT参与神经病理性疼痛的发病机制。癌性骨痛发病机理复杂,治疗效果不理想。神经钙蛋白是NFAT最重要上游调控蛋白，是否参与癌性骨痛的发病机制，未见报道。我们的前期研究发现，神经钙蛋白抑制剂能减轻大鼠的癌性骨痛，我们期待神经钙蛋白能够成为治疗癌性骨痛的新靶点。本研究采用免疫组化,Western Blot,PCR检测大鼠癌性骨痛中，大脑PAG，脊髓和DRG神经钙蛋白和NFAT的表达变化情况，研究两者对胞内MAPKs信号通路和疼痛相关炎性因子的影响，探讨神经钙蛋白和NFAT的抑制剂与阿片类药物,局麻药,NMDA受体拮抗剂，NSAIDs药物之间治疗癌性骨痛的相互作用，为临床治疗癌性骨痛提供新的靶点和理论依据。

Calcineurin play various roles in modulating nociception on intracellular-nucleus sensory signaling pathway. Its most important downstream transcription factor is NFAT. NFAT was upregulated in rats neuropathic pain model of spinal nerve ligation and inhibition of the upregulation of NFAT attenuated the tactile allodynia. These findings suggest that NFAT was involved in the pathogenesis of neuropathic pain. Cancer-induced bone pain pathogenesis is still not clear and clinical treatment is very difficult. There was not any report about that whether the calcineurin was involved in the pathogenesis of cancer-induced bone pain or not, even calcineurin was the most important upstream regulatory proteins of NFAT. Our preliminary results showed that intrathecal injection of calcineurin inhibitor can alleviate the cancer-induced bone pain. Therefore, it is possible for calcineurin to be a new target for the treatment of cancer-induced bone pain. In this study, we examine the expression of calcineurin and NFAT in PAG, spinal cord and DRG under cancer-induced bone pain. Next we explore the antinociception of the inhibitor of calcineurin or inhibitor of NFAT against cancer-induced bone pain. We also evaluate the relationship between calcineurin or NFAT with MAPKS signaling pathways and pain-related inflammatory factors under cancer-induced bone pain. We still explore the interaction between calcineurin inhibitor or NFAT inhibitor with opioids, local anesthetics, NMDA receptor antagonists, NSAIDs in the treatment of cancer-induced bone pain. It will provide a new target and theoretical for the clinical treatment of cancer-induced bone pain.