Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons.
Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons.
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Calpain-2 通过上调 DRG 神经元中的白细胞介素 6 来导致运动神经损伤后的神经性疼痛。
DOI：
10.1016/j.bbi.2014.08.003
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Liu Xian-Guo
中科院分区：
文献类型：
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作者：
Zang Ying;Chen Shao-Xia;Liao Guang-Jie;Zhu He-Quan;Wei Xu-Hong;Cui Yu;Na Xiao-Dong;Pang Rui-Ping;Xin Wen-Jun;Zhou Li-Jun;Liu Xian-Guo
L5腹侧根横断（L5- vrt）引起的运动神经损伤引起初级传入系统中白细胞介素-6 （IL-6）的上调，从而导致神经性疼痛。然而，IL-6在L5-VRT后的早期上游调控机制尚不清楚。在这里，我们监测了钙依赖性蛋白酶calpain（一种被认为是细胞因子调节的最早介质之一）的活性，以及L5-VRT后不久双侧L4-L6背根神经节（DRGs）中IL-6的表达。我们发现，在L5-VRT后，早在机械性异常性疼痛开始前，DRGs中calpain-2蛋白水平（同侧5-15小时，对侧15小时）在同侧10分钟−1h和对侧20分钟−1h内短暂升高，而calpain-1蛋白水平则没有升高。通过谱蛋白分解产物（SBDP）的产生来评估calpain的早期激活与双侧DRGs中IL-6的上调密切相关。双免疫荧光染色显示，几乎所有calpain-2阳性神经元均表达IL-6，提示calpain-2与IL-6存在关联。MDL28170预处理（25 mg/kg, ig）对calpain的抑制作用减弱了大鼠机械异常性痛，阻止了L5-VRT后IL-6的早期上调。在左L5 DRG表面添加外源性calpain-2可触发颞异常性疼痛，同时增加双侧DRG中的IL-6。综上所述，L5-VRT大鼠早期calpain-2升高可能是通过上调DRG神经元中IL-6诱导异位性疼痛的原因。
Motor nerve injury by L5 ventral root transection (L5-VRT) initiates interleukin-6 (IL-6) up-regulation in primary afferent system contributing to neuropathic pain. However, the early upstream regulatory mechanisms of IL-6 after L5-VRT are still unknown. Here, we monitored both the activity of calpain, a calcium-dependent protease suggested as one of the earliest mediators for cytokine regulation, and the expression of IL-6 in bilateral L4–L6 dorsal root ganglias (DRGs) soon after L5-VRT. We found that the protein level of calpain-2 in DRGs, but not calpain-1 was increased transiently in the first 10 min−1h ipsilaterally and 20 min−1h contralaterally after L5-VRT, long before mechanical allodynia was initiated (5–15 h ipsilaterally and 15 h−1d contralaterally). The early activation of calpain evaluated by the generation of spectrin breakdown products (SBDP) correlated well with IL-6 up-regulation in bilateral DRGs. Double immunofluorescence staining revealed that almost all the calpain-2 positive neurons expressed IL-6, indicating an association between calpain-2 and IL-6. Inhibition of calpain by pre-treatment with MDL28170 (25 mg/kg, i.p.) attenuated the rat mechanical allodynia and prevented the early up-regulation of IL-6 following L5-VRT. Addition of exogenous calpain-2 onto the surface of left L5 DRG triggered a temporal allodynia and increased IL-6 in bilateral DRGs simultaneously. Taken together, the early increase of calpain-2 in L5-VRT rats might be responsible for the induction of allodynia via up-regulating IL-6 in DRG neurons.