Connexin 43 Mediates CXCL12 Production from Spinal Dorsal Horn to Maintain Bone Cancer Pain in Rats
Connexin 43 Mediates CXCL12 Production from Spinal Dorsal Horn to Maintain Bone Cancer Pain in Rats
复制标题
DOI：
10.1007/s11064-015-1815-7
复制
发表时间：
2016-05-01
影响因子：
4.4
通讯作者：
Shao, Dong-Hua
中科院分区：
文献类型：
--
作者：
Hang, Li-Hua;Li, Shu-Na;Shao, Dong-Hua
肿瘤转移至骨可随后导致骨癌痛（BCP）。目前，由于对潜在机制了解甚少，BCP 很难攻克。多项研究表明星形胶质细胞特异性连接蛋白 43 (Cx43) 与神经性疼痛有关，并且 Cx43 诱导骨髓基质细胞释放趋化因子 CXCL12。然而，脊髓Cx43是否介导CXCL12的产生来参与BCP的维持仍不清楚。在这里，我们表明，将 Walker 256 肿瘤细胞接种到胫骨中会引起显着的机械异常性疼痛，并伴随着接种后第 6 天至第 18 天脊髓 p-Cx43 和 CXCL12 表达水平的上调。脊髓 Cx43 主要在星形胶质细胞中表达，接种后第 18 天，鞘内注射 (43)Gap26（一种选择性 Cx43 阻滞剂）可显着减轻机械性异常性疼痛，并减少 p-Cx43 和 CXCL12 的表达。 CXCL12 的鞘内给药几乎消除了 (43)Gap26 减弱的机械异常性疼痛。此外，鞘内注射抗CXCL12中和抗体可以改善机械异常性疼痛，同时抑制CXCL12表达的上调，但不影响p-Cx43表达。我们的结果表明，Cx43 介导星形胶质细胞脊髓背角产生 CXCL12，以维持大鼠的骨癌疼痛。这些发现可能会提高我们对 BCP 潜在机制的理解，并为 BCP 的治疗提供新的靶点。
Tumor metastasis to bone can subsequently lead to bone cancer pain (BCP). Currently, BCP is difficult to conquer due to a poor understanding of the potential mechanisms. Several studies have indicated that astrocyte-specific connexin 43 (Cx43) was involved in the neuropathic pain, and Cx43 induced the release of chemokine CXCL12 in bone marrow stromal cells. However, whether spinal Cx43 mediates the production of CXCL12 to participate in the maintenance of BCP is still unknown. Here we showed that Walker 256 tumor cells inoculation into the tibia induced a significant mechanical allodynia, which was accompanied by upregulation of spinal p-Cx43 and CXCL12 expression levels from day 6 to day 18 after inoculation. Spinal Cx43 was mainly expressed in astrocytes, and intrathecal (43)Gap26 (a selective Cx43 blocker) markedly attenuated mechanical allodynia as well as reduced p-Cx43 and CXCL12 expression at day 18 after inoculation. Pre-intrathecal administration of CXCL12 almost abolished the attenuated mechanical allodynia by (43)Gap26. Furthermore, intrathecal injection of anti-CXCL12 neutralizing antibody could ameliorate mechanical allodynia with concomitant inhibition of upregulation of CXCL12 expression, but not influence on p-Cx43 expression. Our results indicate that Cx43 mediates CXCL12 production from spinal dorsal horn in astrocytes to maintain bone cancer pain in rats. These findings may improve our understanding of the underlying mechanisms of BCP and provide a novel target for the treatment of BCP.