Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yet-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China.
Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yet-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China.
Brain Behav Immun. 2014 May;38:185-91. doi: 10.1016/j.bbi.2014.01.020. Epub 2014 Feb 13.
Bortezomib (BTZ) is a frequently used chemotherapeutic drug for the treatment of refractory multiple myeloma and hematological neoplasms. The mechanism by which the administration of BTZ leads to painful peripheral neuropathy remains unclear. In the present study, we first determined that the administration of BTZ upregulated the expression of TNF-α and phosphorylated JNK1/2 in the dorsal root ganglion (DRG) of rat. Furthermore, the TNF-α synthesis inhibitor thalidomide significantly blocked the activation of both isoforms JNK1 and JNK2 in the DRG and attenuated mechanical allodynia following BTZ treatment. Knockout of the expression of TNF-α receptor TNFR1 (TNFR1 KO mice) or TNFR2 (TNFR2 KO mice) inhibited JNK1 and JNK2 activation and decreased mechanical allodynia induced by BTZ. These results suggest that upregulated TNF-α expression may activate JNK signaling via TNFR1 or TNFR2 to mediate mechanical allodynia following BTZ treatment.
硼替佐米（BTZ）是一种常用于治疗难治性多发性骨髓瘤和血液系统肿瘤的化疗药物。BTZ 给药导致痛性周围神经病的机制尚不清楚。在本研究中，我们首先确定 BTZ 给药上调了大鼠背根神经节（DRG）中 TNF-α 和磷酸化 JNK1/2 的表达。此外，TNF-α 合成抑制剂沙利度胺显著阻断了 DRG 中 JNK1 和 JNK2 两种同工型的激活，并减轻了 BTZ 治疗后的机械性痛觉过敏。TNF-α 受体 TNFR1（TNFR1 KO 小鼠）或 TNFR2（TNFR2 KO 小鼠）表达的敲除抑制了 JNK1 和 JNK2 的激活，并减少了 BTZ 诱导的机械性痛觉过敏。这些结果表明，上调的 TNF-α 表达可能通过 TNFR1 或 TNFR2 激活 JNK 信号转导，介导 BTZ 治疗后的机械性痛觉过敏。
