癌性疼痛是晚期癌症患者常见并发症但镇痛效果欠佳。P2X7受体活化介入疼痛调制，海马体是慢性疼痛信息的处理、异常的情绪和记忆形成的关键部位。本课题组预实验发现大鼠骨癌痛模型中，海马P2X7受体表达上调而PRG-1下调，且两者存在广泛共表达；申请人前期发现海马PRG-1调节突触可塑性、LTP和学习记忆能力，推测海马P2X7受体激活通过抑制PRG-1通路调节突触可塑性从而参与大鼠骨癌痛的调制。本研究拟从以下两方面求证：① P2X7受体激活，导致海马神经元结构和功能可塑性以及大鼠疼痛行为改变；② P2X7受体激活后以CaM/Ca2+为中介抑制PRG-1的功能，最终导致神经元突触可塑性改变、骨癌痛形成和维持，并对其相关的分子机制进行研究。本研究探索P2X7受体调制骨癌痛的新的作用通路——PRG-1信号通路，有助于拓展以P2X7受体、PRG-1为靶点的新的癌性疼痛镇痛和肿瘤转移抑制策略。

Cancer pain is a common complication in terminal cancer patients but the analgesic effect is not good. P2X7 receptor activation is involved in pain modulation. The hippocampus is a key part of chronic pain information processing, abnormal emotions and memory formation. Our preliminary experiment found that the expression of hippocampal P2X7 receptor was up-regulated while PRG-1 was down-regulated in cancer-induced bone pain rats, and both are widespread co-expression. The applicant revealed that PRG-1 regulates synaptic plasticity, LTP, learning and memory ability. We rationally hypothesized that P2X7 receptor activation may regulate synaptic plasticity via PRG-1 pathway to participate in bone cancer pain modulation. To try to test this hypothesis, we aim to verify the following assumptions: (1) activation of P2X7 receptor leads to changes in hippocampal neuronal structural and functional plasticity as well as pain behavior in rats; (2) P2X7 receptor activation inhibits PRG-1 function via CaM/Ca2+ and eventually leads to changes in synaptic plasticity of neurons and development of bone cancer pain. We also attempt to clarify the relevant molecular mechanisms. In this study, a new pathway of P2X7 receptor modulating bone cancer pain -- PRG-1 signaling pathway was explored, which is helpful to expand the new cancer pain analgesia strategies targeting P2X7 receptor and PRG-1.