三氯化碳
痛觉超敏
紫杉醇
医学
神经病理性疼痛
周围神经病变
小胶质细胞
趋化因子受体
药理学
脊髓
趋化因子
CXCR4拮抗剂
痛觉过敏
麻醉
免疫学
伤害
化疗
内科学
受体
内分泌学
炎症
四氯化碳
精神科
糖尿病
作者
Ryutaro Ochi-ishi,K. Nagata,Tomoyuki Inoue,Hidetoshi Tozaki‐Saitoh,Masayuki Tsuda,Kazuhide Inoue
标识
DOI:10.1186/1744-8069-10-53
摘要
Background: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. Findings: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 P2×7 receptors (P2×7Rs), which have been implicated in the release of CCL3 from microglia, in the SDH. The selective P2×7R antagonist A438079 had preventive and reversal effects on paclitaxel-induced allodynia. Conclusions:Our findings suggest a contribution of CCL3 and P2×7Rs in the SDH to paclitaxel-induced allodynia and may provide new therapeutic targets for paclitaxel-induced painful neuropathy.
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