酸感受离子通道在骨癌痛发生发展中的作用

Bone pain is one of the most common complications in cancer patients with bone metastases. Pain causes significant influences on the quality of life (QOL) of patients, the mechanism of cancer-associated bone pain is poorly understood, and currently-available therapies for bone pain are inadequate and ineffective or cause uncomfortable adverse effects.. It has been known that activation of osteoclasts and hypermetabolism produced acidic conditions play a central role in the development and progression of bone cancer pain. Our study showed that the sensory nociceptive neurons innervate bone and these neurons express acid-sensing nociceptors such as the acid-sensing ion channels. Acid signals received by these nociceptors subsequently activate intracellular signaling pathways and transcription factors in sensory neurons. The understanding of the nociceptive events following proton release and subsequent creation of acidic microenvironments leads us to design novel molecular-based approaches, including the establishment of animal models of bone pain, appropriate quantitative assessments for bone pain, the examination of the expression of ASICs in the primary aferent neuron DRG and spinal cord, neurochemical nociceptive markers, the extent of osteoclastic bone destruction, the role of ASICs in the synaptic plasticity in spinal dorsal horn during the generation and maintenance of bone cancer pain, the role of ASIC3 in Cutaneous Hyperalgesia. To objective and quantitative evaluate the role of ASIC3 in the procession of pain, may allow us to further understand the pathophysiology of pain at cellular and molecular levels. ASIC3 may prove to be a potential therapeutic target for bone cancer pain.

骨癌痛常见于骨癌或其它晚期肿瘤的骨转移，疼痛常较严重而影响病人生命质量。因其发生机制复杂目前尚无有效治疗措施。目前认为肿瘤诱导破骨细胞激活以及高代谢导致细胞内外酸性微环境对于疼痛的发生至关重要。骨组织局部pH值的降低可直接作用于伤害性感受器上的H+敏感性通道，敏化或兴奋骨膜的初级传入神经而诱发疼痛。本研究拟采用大鼠骨转移癌疼痛模型，深入研究骨癌病程各时点动物疼痛的行为学和组织学改变，初级传入纤维各型ASICs通道的分布表达情况，并着重分析骨癌痛发生过程中ASIC1a在脊髓突触可塑性改变中的可能作用，外周DRG细胞内钙信号的变化，以及ASIC3电流激活特征、激活条件及其与疼痛进程的相关性；初步阐明ASIC3或其他ASIC异聚体在骨癌痛外周伤害信号产生、传导和敏化的作用，加深对骨癌痛发生机制的理解，有助于发现新的药物靶点，为临床有效缓解疼痛提供有益的实验依据。

骨肿瘤诱导的破骨细胞激活以及高代谢导致的细胞内外酸性微环境对于骨癌痛的发生发展至关重要。骨组织局部pH值的降低可直接兴奋伤害性感受器上的H+敏感性通道，敏化或兴奋外周初级传入神经而诱发疼痛。本研究采用大鼠骨癌痛模型，深入研究了骨癌痛病程各时点动物的行为学和组织学改变，背根神经节ASICs各亚基的分布表达变化，结果表明：1）胫骨内接种Walker256大鼠乳腺癌细胞可成功制备大鼠骨转移癌痛模型，并用于骨癌痛的发病机制研究；2）ASIC3在大直径、中直径和小直径的DRG神经元上都有分布，且随着癌痛的进程，ASIC3的分布表达明显增加；3）同侧DRG神经元ASIC1和ASIC4蛋白在骨癌痛状态下表达升高，ASIC2a亚基的表达不论在同侧还是在对侧均无明显改变。而同侧DRG神经元ASIC1b的表达有显著的减少。本项目研究结果初步证明ASICs参与骨癌痛的发生过程，ASIC3可能参与疼痛的易化，而ASIC1b通道可能抑制疼痛的形成。ASIC3和ASIC1b通道作为潜在的疼痛治疗靶点值得继续深入研究其功能及调控机制。