中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (9): 2067-2074.doi: 10.4103/1673-5374.366490

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

减轻吗啡耐受:抑制高迁移率族蛋白B1释放或AMP依赖的蛋白激酶-血红素加氧酶1信号通路

  

  • 出版日期:2023-09-15 发布日期:2023-03-07
  • 基金资助:
    国家自然科学基金项目(81971047,82073910);江苏省自然科学基金项目(BK20191253);江苏省重点研发计划(社会发展)项目(BE2019732);江苏省医院(南京医科大学附属第一医院)临床能力提升项目(JSPH-511B-2018-8)

Suppressing high mobility group box-1 release alleviates morphine tolerance via the adenosine 5'-monophosphate-activated protein kinase/heme oxygenase-1 pathway

Tong-Tong Lin1, #, Chun-Yi Jiang1, #, Lei Sheng1, #, Li Wan1, Wen Fan1, Jin-Can Li1, Xiao-Di Sun2, Chen-Jie Xu3, Liang Hu1, Xue-Feng Wu4, Yuan Han5, Wen-Tao Liu1, 6, *, Yin-Bing Pan2, *   

  1. 1Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province, China; 2Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; 3Department of Anesthesiology and Pain, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China; 4State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu Province, China; 5Department of Anesthesiology, Eye & ENT Hospital, Fudan University, Shanghai, China; 6Institute of Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China
  • Online:2023-09-15 Published:2023-03-07
  • Contact: Wen-Tao Liu, PhD, painresearch@njmu.edu.cn; Yin-Bing Pan, PhD, panyinbing@sina.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81971047 (to WTL) and 82073910 (to XFW); the Natural Science Foundation of Jiangsu Province, No. BK20191253 (to XFW); Key R&D Program (Social Development) Project of Jiangsu Province, No. BE2019732 (to WTL); and Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University) Clinical Capacity Enhancement Project, No. JSPH-511B-2018-8 (to YBP).

摘要:

吗啡等阿片类药物可用于治疗疼痛,但是长期使用吗啡会产生严重的耐受性。研究显示,高迁移率族蛋白B1可参与神经性或炎症性疼痛,但其在吗啡耐受中的作用尚不得而知。实验以连续7d鞘内注射吗啡建立了吗啡耐受大鼠和小鼠模型,可见吗啡可诱导大鼠脊髓神经元释放大量高迁移率族蛋白B1,而这些高迁移率族蛋白B1可通过激活小胶质细胞中Toll样受体4受体,调节核因子κB p65的磷酸化和白细胞介素1β的产生,进而诱发吗啡耐受。进一步小鼠模型的研究显示,高迁移率族蛋白B1抑制剂甘草甜素减轻慢性吗啡耐受性。最后吗啡耐受小鼠模型或SH-SY5Y细胞模型中,化合物C(AMP依赖的蛋白激酶-抑制剂)和锌原卟啉(血红素加氧酶1抑制剂)都可减少吗啡诱导的高迁移率族蛋白B1的释放,并减少减弱核因子κB p65的磷酸化和白细胞介素1β的产生,并减轻模型小鼠的吗啡耐受。因此提示吗啡可通过AMP依赖的蛋白激酶-血红素加氧酶1信号通路诱导高迁移率族蛋白B1的释放,且抑制该通路可有效改善吗啡耐受性。

https://orcid.org/0000-0001-8732-7927 (Wen-Tao Liu); https://orcid.org/0000-0003-4102-2962 (Yin-Bing Pan)

关键词: 吗啡耐受, 高迁移率族蛋白B1, AMP依赖的蛋白激酶, 血红素加氧酶1, 神经炎症, Toll样受体4, 小胶质细胞, 神经元, 核因子κB p65, 白细胞介素1β

Abstract: Opioids, such as morphine, are the most potent drugs used to treat pain. Long-term use results in high tolerance to morphine. High mobility group box-1 (HMGB1) has been shown to participate in neuropathic or inflammatory pain, but its role in morphine tolerance is unclear. In this study, we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days. We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1. HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4 receptor expression in microglia, thereby inducing morphine tolerance. Glycyrrhizin, an HMGB1 inhibitor, markedly attenuated chronic morphine tolerance in the mouse model. Finally, compound C (adenosine 5′-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin (heme oxygenase-1 inhibitor) alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tolerance, and alleviated morphine tolerance in the mouse model. These findings suggest that morphine induces HMGB1 release via the adenosine 5′-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway, and that inhibiting this signaling pathway can effectively reduce morphine tolerance. 

Key words: adenosine 5′-monophosphate-activated protein kinase, heme oxygenase-1, high mobility group box-1, interleukin-1β, microglia, morphine tolerance, neuroinflammation, neuron, nuclear factor-κB p65, Toll-like receptor 4