Spinal injection of TNF-α-activated astrocytes produces persistent pain symptom mechanical allodynia by releasing monocyte chemoattractant protein-1.
Spinal injection of TNF-α-activated astrocytes produces persistent pain symptom mechanical allodynia by releasing monocyte chemoattractant protein-1.
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DOI：
10.1002/glia.21056
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发表时间：
2010-11-15
期刊：
影响因子：
6.2
通讯作者：
Ji, Ru-Rong
中科院分区：
文献类型：
--
作者：
Gao, Yong-Jing;Zhang, Ling;Ji, Ru-Rong
越来越多的证据表明，脊髓星形胶质细胞通过增加脊髓伤害性神经元的活性，即，中枢致敏但是，星形胶质细胞的激活是否足以诱导慢性疼痛症状的直接证据是缺乏的。我们研究了脊髓注射活化的星形胶质细胞是否以及如何在幼稚小鼠中产生机械性异常性疼痛，这是慢性疼痛的主要特征。脊髓（鞘内）注射星形胶质细胞（从新生小鼠的大脑皮质制备，并短暂刺激肿瘤坏死因子-α（TNF-α）），诱导缩爪阈值大幅降低，表明发生了机械性异常性疼痛。当星形胶质细胞培养物用c-Jun N-末端激酶（JNK）的肽抑制剂D-JNKI-1预处理时，这种异常性疼痛被预防。值得注意的是，星形胶质细胞短时间暴露于TNF-α 15分钟，甚至在TNF-α停药后3小时，也以JNK依赖性方式显著增加了趋化因子单核细胞趋化蛋白-1（MCP-1）的表达和释放。同时，鞘内注射TNF-α诱导脊髓星形胶质细胞表达MCP-1。特别是，由TNF-α激活的星形胶质细胞诱导的机械性异常性疼痛可被MCP-1中和抗体逆转。最后，用MCP-1 siRNA预处理星形胶质细胞可减弱星形胶质细胞诱导的机械性异常性疼痛。总之，我们的结果表明，活化的星形胶质细胞足以通过释放MCP-1在幼稚小鼠中产生持续的疼痛症状。
Accumulating evidence suggests that spinal astrocytes play an important role in the genesis of persistent pain, by increasing the activity of spinal cord nociceptive neurons, i.e., central sensitization. But direct evidence of whether activation of astrocytes is sufficient to induce chronic pain symptoms is lacking. We investigated whether and how spinal injection of activated astrocytes could produce mechanical allodynia, a cardinal feature of chronic pain, in naïve mice. Spinal (intrathecal) injection of astrocytes, which were prepared from cerebral cortexes of neonatal mice and briefly stimulated by tumor necrosis factor-alpha (TNF-α), induced a substantial decrease in paw withdrawal thresholds, indicating the development of mechanical allodynia. This allodynia was prevented when the astrocyte cultures were pre-treated with a peptide inhibitor of c-Jun N-terminal kinase (JNK), D-JNKI-1. Of note a short exposure of astrocytes to TNF-α for 15 minutes dramatically increased the expression and release of the chemokine monocyte chemoattractant protein-1 (MCP-1), even 3 hours after TNF-α withdrawal, in a JNK-dependent manner. In parallel, intrathecal administration of TNF-α induced MCP-1 expression in spinal cord astrocytes. In particular, mechanical allodynia induced by TNF-α-activated astrocytes was reversed by a MCP-1 neutralizing antibody. Finally, pretreatment of astrocytes with MCP-1 siRNA attenuated astrocytes-induced mechanical allodynia. Taken together, our results suggest that activated astrocytes are sufficient to produce persistent pain symptom in naïve mice by releasing MCP-1.
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