Zhu Chao, Tang Jun, Ding Tan, Chen Lei, Wang Wei, Mei Xiao-Peng, He Xiao-Tao, Wang Wen, Zhang Li-Dong, Dong Yu-Lin, Luo Zhuo-Jing
Department of Spine Surgery, Institute of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
Pain. 2017 May;158(5):879-890. doi: 10.1097/j.pain.0000000000000848.
Bone cancer pain has been reported to have unique mechanisms and is resistant to morphine treatment. Recent studies have indicated that neuron-restrictive silencer factor (NRSF) plays a crucial role in modulating the expression of the μ-opioid receptor (MOR) gene. The present study elucidates the regulatory mechanisms of MOR and its ability to affect bone cancer pain. Using a sarcoma-inoculated murine model, pain behaviors that represent continuous or breakthrough pain were evaluated. Expression of NRSF in the dorsal root ganglion (DRG) and spinal dorsal horn was quantified at the transcriptional and translational levels, respectively. Additionally, chromatin immunoprecipitation assays were used to detect NRSF binding to the promoter of MOR. Furthermore, NRSF was genetically knocked out by antisense oligodeoxynucleotide, and the expression of MOR and the effect of morphine were subsequently analyzed. Our results indicated that in a sarcoma murine model, NRSF expression is upregulated in dorsal root ganglion neurons, and the expression of NRSF mRNA is significantly negatively correlated with MOR mRNA expression. Additionally, chromatin immunoprecipitation analysis revealed that NRSF binding to the neuron-restrictive silencer element within the promoter area of the MOR gene is promoted with a hypoacetylation state of histone H3 and H4. Furthermore, genetically knocking down NRSF with antisense oligodeoxynucleotide rescued the expression of MOR and potentiated the systemic morphine analgesia. The present results suggest that in sarcoma-induced bone cancer pain, NRSF-induced downregulation of MOR is involved in the reduction of morphine analgesia. Epigenetically, up-regulation of MOR could substantially improve the effect of system delivery of morphine.
据报道，骨癌疼痛具有独特的机制，且对吗啡治疗有抗性。最近的研究表明，神经元限制性沉默因子（NRSF）在调节μ-阿片受体（MOR）基因的表达中起关键作用。本研究阐明了MOR的调控机制及其影响骨癌疼痛的能力。使用接种肉瘤的小鼠模型，评估了代表持续性或突破性疼痛的疼痛行为。分别在转录和翻译水平上对背根神经节（DRG）和脊髓背角中NRSF的表达进行了定量。此外，采用染色质免疫沉淀试验检测NRSF与MOR启动子的结合情况。此外，通过反义寡脱氧核苷酸对NRSF进行基因敲除，随后分析了MOR的表达及吗啡的作用。我们的结果表明，在肉瘤小鼠模型中，背根神经节神经元中NRSF表达上调，且NRSF mRNA的表达与MOR mRNA的表达呈显著负相关。此外，染色质免疫沉淀分析显示，在组蛋白H3和H4低乙酰化状态下，NRSF与MOR基因启动子区域内的神经元限制性沉默元件的结合增强。此外，用反义寡脱氧核苷酸基因敲低NRSF可挽救MOR的表达并增强全身吗啡镇痛作用。目前的结果表明，在肉瘤诱导的骨癌疼痛中，NRSF诱导的MOR下调参与了吗啡镇痛作用的降低。从表观遗传学角度来看，MOR的上调可显著改善吗啡全身给药的效果。
