Hou Xinran, Weng Yingqi, Ouyang Bihan, Ding Zhuofeng, Song Zongbin, Zou Wangyuan, Huang Changsheng, Guo Qulian
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China.
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China.
Brain Res. 2017 Aug 15;1669:97-105. doi: 10.1016/j.brainres.2017.05.014. Epub 2017 May 27.
Bone cancer pain (BCP) is a common complication with inadequate management in patients suffering from advanced cancer. Histone deacetylase inhibitors showed significant analgesic effect in multiple inflammatory and neuropathic pain models, but their effect in bone cancer pain has never been explored. In this study, we utilized a BCP rat model with intra-tibial inoculation of Walker 256 mammary gland carcinoma cells, which developed progressive mechanical hypersensitivity but not thermal hypersensitivity. Intrathecal application of trichostatin A (TSA), a classic pan-HDAC inhibitor, ameliorated tactile hypersensitivity and enhanced the analgesic effect of morphine in BCP rats. The analgesic effect of TSA was blocked by co-administration of CTAP, a specific MOR antagonist, confirming the involvement of mu-opioid receptor (MOR). A reduction of MOR expression was observed in the lumbar spinal cord of BCP rats and TSA treatment was able to partially reverse it. In vitro study in PC12 cells also demonstrated the dose-dependent enhancement of MOR expression by TSA treatment. Taking all into consideration, we could draw the conclusion that HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in BCP rats, probably by restoring MOR expression in spinal cord.
骨癌疼痛（BCP）是晚期癌症患者中一种常见且治疗不足的并发症。组蛋白去乙酰化酶抑制剂在多种炎症性和神经性疼痛模型中显示出显著的镇痛作用，但它们在骨癌疼痛中的作用从未被探究过。在本研究中，我们利用了一种通过胫骨内接种Walker 256乳腺癌细胞建立的BCP大鼠模型，该模型出现了进行性机械性超敏反应，但未出现热超敏反应。鞘内注射曲古抑菌素A（TSA），一种经典的泛组蛋白去乙酰化酶抑制剂，可改善触觉超敏反应，并增强吗啡对BCP大鼠的镇痛效果。TSA的镇痛作用被共同给予特异性μ-阿片受体（MOR）拮抗剂CTAP所阻断，证实了μ-阿片受体的参与。在BCP大鼠的腰脊髓中观察到MOR表达降低，而TSA治疗能够部分逆转这种情况。在PC12细胞中的体外研究也表明，TSA治疗可剂量依赖性地增强MOR表达。综合考虑所有因素，我们可以得出结论，组蛋白去乙酰化酶抑制剂TSA可改善BCP大鼠的机械性超敏反应并增强吗啡的镇痛效果，可能是通过恢复脊髓中的MOR表达来实现的。
