Tao Wenjuan, Zhou Wenjie, Wang Yuping, Sun Tingting, Wang Haitao, Zhang Zhi, Jin Yan
Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China.
Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China.
Neuroscience. 2016 Dec 17;339:54-63. doi: 10.1016/j.neuroscience.2016.09.015. Epub 2016 Sep 17.
The efficacy of opioids in patients with chronic neuropathic pain remains controversial. Although activation of δ-opioid receptors (DORs) in the brainstem reduces inflammation-induced persistent hyperalgesia, it is not effective under persistent neuropathic pain conditions and these clinical problems remain largely unknown. In this study, by using a chronic constriction injury (CCI) of the sciatic nerve in rats, we found that in the brainstem nucleus raphe magnus (NRM), DORs emerged on the surface membrane of central synaptic terminals on day 3 after CCI surgery and disappeared on day 14. Histone deacetylase (HDAC) inhibitors microinjected into the NRM in vivo increased the level of synaptosomal DOR protein and NRM infusion of DOR agonists producing an antinociceptive effect in a nerve growth factor (NGF) signaling-dependent manner. In vitro, in CCI rat slices incubated with HDAC inhibitors, DOR agonists significantly inhibited EPSCs. This effect was blocked by tyrosine receptor kinase A antagonists. Chromatin immunoprecipitation analysis revealed that NRM infusion of HDAC inhibitors in CCI rats increased the level of histone H4 acetylation at Ngf gene promoter regions. NGF was infused into the NRM or incubated CCI rat slices drove DORs to the surface membrane of synaptic terminals. Taken together, epigenetic upregulation of NGF activity by HDAC inhibitors in the NRM promotes the trafficking of DORs to pain-modulating neuronal synapses under neuropathic pain conditions, leading to δ-opioid analgesia. These findings indicate that therapeutic use of DOR agonists combined with HDAC inhibitors might be effective in chronic neuropathic pain managements.
阿片类药物在慢性神经性疼痛患者中的疗效仍存在争议。尽管脑干中δ-阿片受体（DORs）的激活可减轻炎症诱导的持续性痛觉过敏，但在持续性神经性疼痛条件下却无效，而且这些临床问题在很大程度上仍不清楚。在本研究中，通过对大鼠坐骨神经进行慢性压迫损伤（CCI），我们发现，在脑干中缝大核（NRM），CCI手术后第3天DORs出现在中枢突触终末的表面膜上，并在第14天消失。体内向NRM微量注射组蛋白脱乙酰酶（HDAC）抑制剂可增加突触体DOR蛋白水平，向NRM注入DOR激动剂以神经生长因子（NGF）信号依赖的方式产生抗伤害感受作用。在体外，用HDAC抑制剂孵育CCI大鼠脑片，DOR激动剂可显著抑制兴奋性突触后电流（EPSCs）。这种作用被酪氨酸受体激酶A拮抗剂阻断。染色质免疫沉淀分析显示，CCI大鼠体内向NRM注入HDAC抑制剂可增加Ngf基因启动子区域组蛋白H4的乙酰化水平。向NRM注入NGF或孵育CCI大鼠脑片可使DORs转运至突触终末的表面膜。综上所述，HDAC抑制剂在NRM中对NGF活性的表观遗传上调促进了神经性疼痛条件下DORs向疼痛调节神经元突触的转运，从而导致δ-阿片类镇痛。这些发现表明，联合使用DOR激动剂和HDAC抑制剂进行治疗可能对慢性神经性疼痛的管理有效。
