Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia.
Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia.
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DOI：
10.1186/1744-8069-10-53
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发表时间：
2014-08-15
期刊：
影响因子：
3.3
通讯作者：
Inoue K
中科院分区：
文献类型：
--
作者：
Ochi-ishi R;Nagata K;Inoue T;Tozaki-Saitoh H;Tsuda M;Inoue K
紫杉醇是一种有效的化疗药物，广泛用于治疗实体瘤。紫杉醇的主要剂量限制性毒性是周围神经病变。紫杉醇诱导的周围神经病变的发生和维持机制尚不清楚，目前尚无有效的治疗方法。在周围神经损伤的神经性疼痛模型中，越来越多的证据表明脊髓小胶质细胞和趋化因子参与疼痛超敏反应，但对它们在化疗诱导的周围神经病变中的作用知之甚少。在本研究中，我们研究了CC-趋化因子配体3（CCL 3）在脊髓中的作用，在开发和维护机械异常性疼痛使用大鼠模型紫杉醇诱导的神经病变。紫杉醇重复静脉给药诱导对机械刺激（机械性异常性疼痛）作出反应的缩爪阈值显著降低。在这些大鼠中，脊髓背角（SDH）中的小胶质细胞数量显著增加。紫杉醇治疗的大鼠表现出CCL 3及其受体CCR 5在SDH中的mRNA表达显著增加。鞘内注射CCL 3中和抗体不仅可以减弱紫杉醇诱导的机械性异常性疼痛的发展，而且可以逆转其维持。紫杉醇还上调了SDH中嘌呤受体P2 X7受体（P2 X7 Rs）的表达，该受体与小胶质细胞释放CCL 3有关。选择性P2 X7 R拮抗剂A438079对紫杉醇诱发的痛觉超敏具有预防和逆转作用。我们的研究结果表明，CCL 3和P2 X7 Rs在SDH的贡献，紫杉醇诱导的异常性疼痛，并可能提供新的治疗靶点紫杉醇诱导的疼痛性神经病变。
Paclitaxel is an effective chemotherapeutic agent widely used for the treatment of solid tumors. The major dose-limiting toxicity of paclitaxel is peripheral neuropathy. The mechanisms underlying the development and maintenance of paclitaxel-induced peripheral neuropathy are still unclear, and there are no currently established effective treatments. Accumulating evidence in models of neuropathic pain in which peripheral nerves are lesioned has implicated spinal microglia and chemokines in pain hypersensitivity, but little is know about their roles in chemotherapy-induced peripheral neuropathy. In the present study, we investigated the role of CC-chemokine ligand 3 (CCL3) in the spinal cord in the development and maintenance of mechanical allodynia using a rat model of paclitaxel-induced neuropathy. Repeated intravenous administration of paclitaxel induced a marked decrease in paw withdrawal threshold in response to mechanical stimulation (mechanical allodynia). In these rats, the number of microglia in the spinal dorsal horn (SDH) was significantly increased. Paclitaxel-treated rats showed a significant increase in the expression of mRNAs for CCL3 and its receptor CCR5 in the SDH. Intrathecal administration of a CCL3-neutralizing antibody not only attenuated the development of paclitaxel-induced mechanical allodynia but also reversed its maintenance. Paclitaxel also upregulated expression of purinoceptor P2X7 receptors (P2X7Rs), which have been implicated in the release of CCL3 from microglia, in the SDH. The selective P2X7R antagonist A438079 had preventive and reversal effects on paclitaxel-induced allodynia. Our findings suggest a contribution of CCL3 and P2X7Rs in the SDH to paclitaxel-induced allodynia and may provide new therapeutic targets for paclitaxel-induced painful neuropathy.
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