鞘内注射p38MAPK抑制剂对乳腺癌骨转移大鼠疼痛行为及前炎性细胞因子表达的影响

Effects of p38MAPK kinase inhibitor by intrathecal injection on the rat pain behavior and proinflammatory cytoldnes in a metastatic bone cancer pain model

目的观察鞘内注射p38丝裂原活化蛋白激酶（MAPK）抑制剂SB203580对乳腺癌骨转移大鼠疼痛行为及前炎性细胞因子的影响。方法成功制备骨转移疼痛模型SD大鼠11只，随机取6只（给药组）鞘内注射p38MAPK抑制剂SB203580，另5只设为对照。分别检测两组动物胫骨破坏程度、热刺激后爪退缩潜伏期（PWL）、脊髓白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）mRNA表达及蛋白含量。结果11只大鼠均出现明显骨破坏伴左后肢热痛觉敏感性增加。给药组与对照组大鼠胫骨破坏程度无差异，但给药组大鼠左侧PWL值[16d：（12．12±1．26）s；19d：（12．99±1．65）s]显著高于对照组[16d：（9．05±1．08）s；19d：（8．55±1．60）s，P〈0．05]；左侧脊髓内IL-1β和TNF—α mRNA表达减少、蛋白含量降低（P〈0．05）。结论骨转移癌痛大鼠鞘内注入SB203580不能阻止胫骨进一步破坏，但可以明显降低热痛敏感性，这可能与其抑制脊髓水平P38MAPK信号通路，降低了前炎性细胞因子IL-1β和TNF-α的表达有关。

Objective To observe the effects of p38 mitogen activated protein kinase （MAPK） inhibitor SB203580 by intrathecal injection on the pain behavior and the spinal proinflammatory cytokines in a rat model of bone cancer pain induced by breast cancer cells. Mαhods Eleven rats were used to establish the models of bone cancer pain,6 rats were treated by intrathecal SB203580 injection,and the remaining 5 served as the controls. The paw withdrawal latency （PWL） , histology and the spinal levels of IL-1β and TNF-α were dαected. Results All the 11 rats presented evident bone destruction and thermal hyperalgesia. No effect of SB203580 on the bone destruction was observed. However,following intrathecal injection of SB203580, the left PWLs [ （ 12.12 ± 1.26） s at 16th day and （ 12.99 ± 1.65 ） s at 19th day ] were significantly higher than that of controls [ （9.05 ± 1.08 ） s at 16th day and （ 8.55 ± 1.60） s at 19th days ,P 〈 0.05 ]. Meanwhile,intrathecal injection of SB203580 evidently reduced the levels of spinal IL-1 β and TNF-α. Conclusion Intrathecal injection of SB203580 in a rat model of bone cancer pain cannot prevent the tibial destruction but significantly depress the thermalgia sensitivity, which might result from the inhibition of intracellular p38MAPK signal transduction, and thereby reducing the release of the proinflammatory cytokines.