Extracellular signal-regulated kinase activation in spinal astrocytes and microglia contributes to cancer-induced bone pain in rats
Extracellular signal-regulated kinase activation in spinal astrocytes and microglia contributes to cancer-induced bone pain in rats
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DOI：
10.1016/j.neuroscience.2012.04.065
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发表时间：
2012-08
期刊：
影响因子：
3.3
通讯作者：
X.-W. Wang;T. Li;Jing Zhao;Q. Mao-Ying;H. Zhang;S. Hu;Qian Li;W. Mi;Gen-cheng Wu;Yu Zh
中科院分区：
文献类型：
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作者：
X.-W. Wang;T. Li;Jing Zhao;Q. Mao-Ying;H. Zhang;S. Hu;Qian Li;W. Mi;Gen-cheng Wu;Yu Zh
癌症疼痛，特别是癌症引起的骨痛，影响癌症患者的生活质量，目前对这种疼痛的治疗是有限的。目前的研究表明，脊髓细胞外信号调节激酶（ERK）在神经胶质细胞中的激活在癌症诱导的骨痛中起着至关重要的作用。在小鼠胫骨内接种Walker 256乳腺癌细胞后的第4天至第21天，von Frey毛发试验中机械退出阈值的降低表明小鼠出现了明显的机械异常性疼痛。在胫骨内接种癌细胞诱导了双侧L2-L3和L4-L5脊髓背角ERK的广泛和持续（bbbb21 D）激活。在表达iba -1的小胶质细胞和表达gmap -星形胶质细胞中均观察到perk1 /2免疫反应性增加，但在表达neun的神经元中未观察到。在von Frey毛发试验中，单次鞘内注射选择性MEK （ERK激酶）抑制剂PD98059 (10μg)（第12天）和U0126(1.25和3μg)（第14天）可减轻双侧机械异位性痛。总之，我们的研究结果表明，脊髓小胶质细胞和星形胶质细胞中的ERK激活与异常性疼痛的发生有关，并且对癌性疼痛模型中异常性疼痛的维持很重要。本研究提示抑制ERK通路可能为癌症性骨痛提供一种新的治疗方法。
Cancer pain, especially cancer-induced bone pain, affects the quality of life of cancer patients, and current treatments for this pain are limited. The present study demonstrates that spinal extracellular signal-regulated kinase (ERK) activation in glial cells plays a crucial role in cancer-induced bone pain. From day 4 to day 21 after the intra-tibia inoculation with Walker 256 mammary gland carcinoma cells, significant mechanical allodynia was observed as indicated by the decrease of mechanical withdrawal thresholds in the von Frey hair test. Intra-tibia inoculation with carcinoma cells induced a vast and persistent (>21 D) activation of ERK in the bilateral L2–L3 and L4–L5 spinal dorsal horn. The increased pERK1/2-immunoreactivity was observed in both Iba-1-expressing microglia and GFAP-expressing astrocytes but not in NeuN-expressing neurons. A single intrathecal injection of the selective MEK (ERK kinase) inhibitors PD98059 (10μg) on day 12 and U0126 (1.25 and 3μg) on day 14, attenuated the bilateral mechanical allodynia in the von Frey hair test. Altogether, our results suggest that ERK activation in spinal microglia and astrocytes is correlated with the onset of allodynia and is important for allodynia maintenance in the cancer pain model. This study indicated that inhibition of the ERK pathway may provide a new therapy for cancer-induced bone pain.