NRG1-ErbB2信号通路对骨癌痛大鼠脊髓胶质细胞及IL-1β的影响

Effect of NRG1-ErbB2 signaling pathway on spinal cord glia and IL-1β of rats with cancer-induced bone pain

目的探讨NRG1-Erb B2信号通路对骨癌痛大鼠脊髓胶质细胞和IL-1β的影响。方法雌性SD大鼠,随机分为3组,每组12只。Sham组(假手术组);CIBP组:大鼠胫骨内注射Walker256乳腺癌细胞构建骨癌痛模型;CIBP+PD168393组:构建CIBP模型后6 d,鞘内注入PD168393 10μg,每日1次,连续9 d,其余组鞘内注入生理盐水。接种瘤细胞后14 d,检测大鼠脊髓背角GFAP、OX42和IL-1β的变化。结果接种瘤细胞后14 d,CIBP组大鼠GFAP、OX42积分光密度值明显高于Sham组,差异有统计学意义(P<0.01),肿瘤细胞的植入能诱导大鼠同侧脊髓背角GFAP和OX42的表达显著增加,并使星形胶质细胞和小胶质细胞的胞体肥大。而给予Erb B2受体抑制剂PD168393可明显抑制脊髓背角神经化学物质的改变,GFAP和OX42的表达均明显降低(P<0.01)。CIBP组IL-1β于接种瘤细胞后14 d表达增加,明显高于Sham组(P<0.01),给予PD168393能显著抑制IL-1β表达增加(P<0.01)。结论大鼠胫骨接种瘤细胞后,脊髓背角内星形胶质细胞和小胶质细胞被广泛激活,IL-1β释放增加,阻断NRG1-Erb B2受体信号通路能有效抑制脊髓胶质细胞的表达和活化及炎症介质IL-1β的释放,从而产生镇痛作用。

Objective To investigate the effect of neuregulinl（NRG1）-ErbB2 signaling pathway on the expression of spinal cord glia and IL-1β in rats with cancer-induced bone pain（CIBP）.Methods Female SD rats were randomly divided into three groups（12 rats in each group）.Sham group：sham operation group.CIBP group：walker256mammary gland carcinoma cell was inoculated into the tibia of rats.CIBP ＋ PD168393 group：10 μg PD168393 was injected intrathecally once daily at 6 d after inoculation for 9 d.Intrathecal injection of saline was given in another groups.The expression of Glial fibrillary acidic protein（GFAP）,OX42 and IL-1β was detected at 14 d after inoculation.Results The mean optical density of OX42 and GFAP in CIBP group was higher than that of sham group at 14 d after inoculation（P 〈0.01）.The inoculation of walker256 tumor cell could significantly increase the expression of GFAP and OX42 in ipsilateral spinal cord dorsal,make the astrocytes and microglia hypertrophy.The alterations were inhibited by PD168393,an ErbB2 receptor blocking agent,and the GFAP and OX42 expression decreased（P 〈0.01）.The expression of IL-1β in CIBP group was higher than that of sham group at 14 d after inoculation（P 〈0.01）,which was attenuated by PD168393.Conclusion Tumor cell inoculation induces the activation of spinal astrocytes and mi—croglia and promotes the release of IL-1β.Inhibiting NRG1-ErbB2 signaling pathway can reduce the CIBP by suppressing the activation of spinal glia and the expression of inflammatory cytokine IL-1β.