Targeting P2X7 receptor for the treatment of central post-stroke pain in a rodent model
Targeting P2X7 receptor for the treatment of central post-stroke pain in a rodent model
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DOI：
10.1016/j.nbd.2015.02.028
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发表时间：
2015-06-01
影响因子：
6.1
通讯作者：
Shyu, Bai-Chuang
中科院分区：
文献类型：
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作者：
Kuan, Yung-Hui;Shih, Hsi-Chien;Shyu, Bai-Chuang
中风是工业化国家死亡和残疾的主要原因。当出血性中风发生在丘脑外侧区域时，大约 8-14% 的中风幸存者会遭受中枢性中风后疼痛 (CPSP)，这严重影响了他们的生活质量。由于 CPSP 的机制尚不清楚，因此尚未开发出有效的治疗方法。在本研究中，我们检验了以下假设：持续性 CPSP 是由脑组织损伤后 P2X7 受体激活和随后炎症细胞因子升高引起的。使用丘脑出血大鼠模型，其特征是在 CPSP 发作时在亚急性至慢性阶段出现热和机械异常性疼痛。我们发现出血后 5 周时丘脑笔病变组织中反应性小胶质细胞/巨噬细胞中 P2X7 的表达显着增加。丘脑 P2X7 受体直接参与疼痛传递和超敏反应。在出血急性期全身靶向 P2X7 受体可通过减少反应性小胶质细胞/巨噬细胞聚集和相关炎症细胞因子来挽救丘脑扣带回通路中的异常疼痛行为和神经元活动。 CPSP 发病后，白细胞介素 1β 的靶向逆转了异常的疼痛敏感性。通过阻断 P2X7 受体来调节 CPSP 大鼠异常的自发丘脑皮质振荡。综上所述，我们的结果表明，靶向 P2X7 在 CPSP 的治疗中可能具有双效作用，既可以作为疼痛阻滞剂，又可以作为免疫抑制剂，抑制脑组织的炎症损伤。 P2X7受体可能作为预防CPSP发生的潜在靶点，并可能有益于中风患者的康复。 (C) 2015 Elsevier Inc. 保留所有权利。
Stroke is a leading cause of death and disability in industrialized countries. Approximately 8-14% of stroke survivors suffer from central post-stroke pain (CPSP) when hemorrhagic stroke occurs in lateral thalamic regions, which severely affects their quality of life. Because the mechanisms of CPSP are not well understood, effective treatments have not been developed. In the present study, we tested the hypothesis that persistent CPSP is caused by P2X7 receptor activation after brain tissue damage and subsequent elevations in inflammatory cytokines. A thalamic hemorrhagic rat model was used, characterized by thermal and mechanical allodynia that develops in the subacute to chronic phases upon CPSP onset. We found a significant increase in P2X7 expression in reactive microglia/macrophages in thalamic pen-lesion tissues at 5 weeks post-hemorrhage. Thalamic P2X7 receptors were directly involved in pain transmission and hypersensitivity. The systemic targeting of P2X7 receptors during the acute stage of hemorrhage rescued abnormal pain behaviors and neuronal activity in the thalamocingulate pathway by reducing reactive microglia/macrophage aggregation and associated inflammatory cytokines. After CPSP onset, the targeting of interleukin-1 beta reversed abnormal pain sensitivity. The aberrant spontaneous thalamocortical oscillations in rats with CPSP were modulated by blocking P2X7 receptors. Taken together, our results suggest that targeting P2X7 may be bi-effective in the treatment of CPSP, as both a pain blocker and immunosuppressant that inhibits inflammatory damage to brain tissue. P2X7 receptors may serve as a potential target to prevent the occurrence of CPSP and may be beneficial for the recovery of patients from stroke. (C) 2015 Elsevier Inc. All rights reserved.