CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord.
CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord.
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DOI：
10.1186/1742-2094-11-75
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发表时间：
2014-04-16
影响因子：
9.3
通讯作者：
Song C
中科院分区：
文献类型：
--
作者：
Shen W;Hu XM;Liu YN;Han Y;Chen LP;Wang CC;Song C
以往的研究表明趋化因子CXCL 12及其受体CXCR 4在疼痛致敏中起关键作用，但其机制尚不清楚。在这项研究中，我们研究了CXCL 12/CXCR 4趋化因子信号在肿瘤细胞植入（TCI）后骨癌疼痛的发展和维持中的特定细胞机制。采用大鼠胫骨腔内靶控注射建立骨癌痛模型。机械异常性疼痛和热痛觉过敏分别通过测量缩爪阈值和潜伏期来确定。Western blot和免疫荧光染色检测CXCL 12和CXCR 4蛋白表达和细胞定位。通过观察c-Fos、GFAP和IBA 1的免疫荧光强度来检测神经元的敏化、星形胶质细胞和小胶质细胞的活化。我们的研究结果表明，CXCL 12上调的时间相关的方式，无论是在背根神经节和脊髓后TCI。脊髓CXCL 12主要在星形胶质细胞中表达，鞘内注射星形胶质细胞代谢抑制剂氟柠檬酸盐或选择性JNK抑制剂SP 600125消除了TCI诱导的CXCL 12产生。TCI后第10天单次鞘内注射CXCL 12中和抗体（10 μg/10 μl）以剂量依赖性方式短暂逆转骨癌疼痛。而重复鞘内注射CXCL 12中和抗体（10 μg/10 μl，TCI后第3 - 5天每天一次）可显著延迟TCI诱导的疼痛行为发作近5天。脊髓CXCR 4在TCI后也上调，并与神经元、星形胶质细胞和小胶质细胞共定位。在第14天，阻断CXCR 4抑制脊髓中神经元、星形胶质细胞和小胶质细胞的TCI诱导的活化。在骨癌的早期阶段（TCI后第5、6和7天）和晚期阶段（TCI后第12、13和14天），重复鞘内注射AMD 3100（5 μg/10 μl，每天一次，持续3天）分别显著延迟和抑制骨癌疼痛的开始和持续。综上所述，这些结果表明，CXCL 12/CXCR 4信号转导通过致敏神经元和激活星形胶质细胞和小胶质细胞促进骨癌疼痛的发展和维持。此外，这种趋化因子信号传导可能是治疗骨癌疼痛的潜在靶点。
Previous studies have demonstrated that chemokine CXCL12 and its receptor CXCR4 are critical for pain sensitization, but the mechanisms involved are not clear. In this study, we investigated the specific cellular mechanisms of CXCL12/CXCR4 chemokine signaling in the development and maintenance of bone cancer pain after tumor cell implantation (TCI). TCI in the tibial cavity of rats was used to establish a bone cancer pain model. Mechanical allodynia and thermal hyperalgesia were determined by measuring the paw withdrawal threshold and latency, respectively. The protein expression and cellular localization of CXCL12 and CXCR4 were detected by western blot and immunofluorescence staining. The sensitization of neurons, activation of astrocytes and microglia were examined by observing the immunofluorescence intensity of c-Fos, GFAP and IBA1. Our results demonstrated that CXCL12 was upregulated in a time-related manner, both in the dorsal root ganglia and spinal cord after TCI. Spinal CXCL12 was predominately expressed in astrocytes, and an intrathecal injection of astrocyte metabolic inhibitor fluorocitrate or selective JNK inhibitor SP600125 abolished TCI-induced CXCL12 production. A single intrathecal injection of a CXCL12 neutralizing antibody (10 μg/10 μl) at day 10 after TCI transiently reversed bone cancer pain in a dose-dependent manner. Whereas repetitive intrathecal administration of a CXCL12 neutralizing antibody (10 μg/10 μl, once a day from day 3 to 5 after TCI) significantly delayed the onset of TCI-induced pain behaviors for nearly five days. Spinal CXCR4 was also upregulated after TCI and colocalized with neurons, astrocytes and microglia. Blocking CXCR4 suppressed TCI-induced activation of neurons, astrocytes and microglia in the spinal cord at day 14. Repeated intrathecal administration of AMD3100 (5 μg/10 μl, once a day for three days) significantly delayed and suppressed the initiation and persistence of bone cancer pain in the early phase (at day 5, 6 and 7 after TCI) and in the late phase (at day 12, 13 and 14 after TCI) of bone cancer, respectively. Taken together, these results demonstrate that CXCL12/CXCR4 signaling contributed to the development and maintenance of bone cancer pain via sensitizing neurons and activating astrocytes and microglia. Additionally, this chemokine signaling may be a potential target for treating bone cancer pain.
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