癌痛是最严重的慢性痛之一，其特性有别于炎症和神经病理性痛。因机理不明，约半数患者得不到有效控制。我们和他人的工作显示，ATP及其受体P2X7是小胶质细胞激活的重要启动分子，但ATP的细胞来源和释放途径仍不清楚。本课题拟采用多学科技术研究癌痛时ATP的细胞来源、释放途径及如何通过激活胶质细胞导致持续性癌痛。主要研究问题包括：1)在大鼠骨癌痛模型上确定癌痛时增强的外周伤害性传入是否直接活化脊髓星形胶质细胞；2)确定星形胶质细胞是否为癌痛时ATP的主要来源，以及其表达的半通道Cx43如何调控ATP的释放；3)ATP如何通过P2X7R激活小胶质细胞；4)胶质细胞释放的胶质递质如何调控神经元的突触传递和可塑性。合作方在胶质细胞相关的条件性转基因动物方面有优势，我方在疾病动物模型和电生理记录技术见长，本合作研究将有助于深入了解胶质细胞通讯在骨癌痛中枢敏化中的特征性作用，为难治性癌痛提供潜在的治疗靶点。

Cancer pain is one of the most severe forms of chronic pain. Currently, pain relief could be clinically achieved only in half of patients suffering from cancer pain, due to our incomplete understanding of cellular and molecular mechanisms underlying the pathogenesis of cancer pain. ATP together with its P2X7 receptor (P2X7R) play a crucial role in the activation of microglia and central sensitization, but the cellular source of ATP is illusive. In this project, using multidisciplinary approaches, we explore the cellular source of ATP, mechanisms of ATP release and how the activation of glial cells could lead to persistent cancer pain. Major question to be addressed are as follows: (1) how bone cancer-induced persistent activation of primary afferents drives astrocyte activation and proliferation, which is followed by microglia activation in the spinal cord; (2) if astrocytes are a major cellular sources of ATP produced during cancer pain and how the hemichannels connexin-43 (Cx43) expressed in astrocytes modulates the release of ATP; (3) how ATP activities microglia via its receptor P2X7R; (4) how glial mediators, such as IL-18 and D-serine, released from microglia and astrocytes, strengthen cancer pain via enhancing synaptic transmission and inducing synaptic plasticity in spinal cord pain circuit. This project will be conducted through a close collaboration between Prof. Yu-Qiu Zhang at Fudan University, who has extensive expertise in animal model and electrophysiology and Prof. Ru-Rong Ji at Duke University, an internationally renowned neuroscientist for studying glial signaling in pain, who will provide assistance to Dr. Prof. Zhang with for glial singling mechanisms, single cell PCR analysis, and transgenic animals. The proposed studies will reveal new insights into the role of astrocyte to microglial signaling in cancer pain, which could eventually lead to development of novel therapeutic strategies for treating cancer pain.