甲基苯基化依赖的HMGB1核输出通过输出蛋白1参与吗啡耐受。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity Pub Date : 2025-08-07 DOI:10.1016/j.bbi.2025.106070

Ying-Ping Liang , Da-Ying Zhang , Dong-Sheng Le , Li Liu , Fan Yang , Shi-Yu Sun , Guo-Rong Lai , Chao Zhang , Mai-Lin Zhao , Ping-Sheng Liao , Tong Liu , Bing Wang

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引用次数: 0

摘要

背景：核细胞质转运与慢性疼痛有关，特别是通过进口蛋白介导的核输入。然而，核出口在阿片类药物诱导的适应中的作用仍不清楚。输出蛋白1 （expouttin 1, XPO1）是一种关键的核输出蛋白，目前尚未在吗啡耐受的背景下进行研究。本研究探讨了XPO1及其与促炎介质在阿片耐受性和痛觉过敏发展中的作用。方法：采用慢性吗啡给药大鼠模型，观察脊髓XPO1表达和活性的变化。通过免疫印迹法评估XPO1及其上游激酶的磷酸化状态。对脑脊液（CSF）进行蛋白质组学分析，以确定与吗啡暴露相关的分泌因子。采用免疫共沉淀法和体外法检测XPO1与高迁移率组盒1 （HMGB1）的相互作用。研究了parp1介导的聚（adp -核糖基）化（PARylation）在HMGB1核输出调控中的作用。行为学分析评估XPO1和PARP1药理抑制对吗啡耐受性和伤害性超敏反应的影响。结果：慢性吗啡暴露导致脊髓神经元XPO1蛋白显著上调，丝氨酸/苏氨酸激酶38 （STK38）磷酸化其1010丝氨酸位点，增强其核输出功能。脑脊液蛋白质组学显示HMGB1水平升高，HMGB1是一种促炎介质。XPO1抑制抑制HMGB1分泌。从机制上讲，parp1介导的HMGB1的PARylation对于其与XPO1的相互作用和随后的核输出至关重要。联合低剂量抑制XPO1和PARP1逆转了已建立的吗啡耐受，减轻了机械超敏反应。然而，鞘内给药重组HMGB1消除了这些作用，恢复了吗啡耐受。结论：这些发现揭示了stk38驱动的XPO1磷酸化和parp1介导的HMGB1修饰在阿片类药物耐受背景下协调核输出和细胞外信号传导的新机制。XPO1和PARP1的双重抑制是抑制神经炎症和增强阿片类镇痛效果的一种有希望的治疗策略。

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Parylation dependent nuclear export of HMGB1 via exportin 1 contributes to morphine tolerance

Background

Nucleocytoplasmic transport has been implicated in chronic pain, particularly through importin-mediated nuclear import. However, the role of nuclear export in opioid-induced adaptations remains unclear. Exportin 1 (XPO1), a key nuclear export protein, has not been studied in the context of morphine tolerance. This study explores the contribution of XPO1 and its interaction with pro-inflammatory mediators in the development of opioid tolerance and hyperalgesia.

Methods

A rat model of chronic morphine administration was used to assess changes in spinal XPO1 expression and activity. Phosphorylation status of XPO1 and upstream kinases were evaluated by immunoblotting. Proteomic analysis of cerebrospinal fluid (CSF) was performed to identify secreted factors associated with morphine exposure. Co-immunoprecipitation and in vitro assays were used to examine the interaction between XPO1 and high mobility group box 1 (HMGB1). The role of PARP1-mediated poly(ADP-ribosyl)ation (PARylation) in regulating HMGB1 nuclear export was also investigated. Behavioral assays were used to assess the impact of pharmacological inhibition of XPO1 and PARP1 on morphine tolerance and nociceptive hypersensitivity.

Results

Chronic morphine exposure led to significant upregulation of XPO1 in spinal neurons, accompanied by phosphorylation at serine 1010 by serine/threonine kinase 38 (STK38), which enhanced its nuclear export function. CSF proteomics revealed elevated levels of HMGB1, a pro-inflammatory mediator. XPO1 inhibition suppressed HMGB1 secretion. Mechanistically, PARP1-mediated PARylation of HMGB1 was essential for its interaction with XPO1 and subsequent nuclear export. Combined low-dose inhibition of XPO1 and PARP1 reversed established morphine tolerance and alleviated mechanical hypersensitivity. However, intrathecal administration of recombinant HMGB1 abolished these effects, reinstating morphine tolerance.

Conclusions

These findings reveal a novel mechanism by which STK38-driven phosphorylation of XPO1 and PARP1-mediated modification of HMGB1 coordinate nuclear export and extracellular signaling in the context of opioid tolerance. Dual inhibition of XPO1 and PARP1 represents a promising therapeutic strategy to suppress neuroinflammation and enhance opioid analgesic efficacy.

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来源期刊

Brain, Behavior, and Immunity 医学-免疫学

CiteScore

29.60

自引率

2.00%

发文量

290

审稿时长

28 days

期刊介绍： Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.