Intermittent Hypoxia Triggers Glial Cell Activation, GluN2B Receptor Upregulation and Hyperalgesia in a Mouse Model of Sleep Apnea

IF 3.5 2区医学 Q1 ANESTHESIOLOGY

European Journal of Pain Pub Date : 2025-06-09 DOI:10.1002/ejp.70039

Yen-Chin Liu, Bo-Ya Chiu, Kuan-Yi Tu, I-Chen Liu, Shiou-Lan Chen

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Abstract

Background

Sleep apnea is a condition that disrupts physiological homeostasis, leading to neuronal dysfunction and triggering a cascade of neurobiological effects. Individuals with sleep apnea and related disturbances may experience increased anxiety and sensory dysfunction, though these phenomena remain underexplored.

Methods

In this study, we used a mouse model to examine the effects of sleep apnea-induced intermittent hypoxia (IH) on sensory function and the mechanisms underlying chronic IH. Mice were exposed to chronic IH for 10 days to assess neuronal inflammation and neuronal plasticity changes in key areas such as the spinal cord and periaqueductal grey (PAG) to understand how IH alters sensory conduction pathways.

Results

Our analysis revealed that in mice exposed to IH, astrocytes and microglia were significantly upregulated in the dorsal and ventral horns of the lower spinal cord, accompanied by elevated cytokine levels (IL-1β and TNF-α), suggesting an inflammatory response. Moreover, a significant increase in astrocyte cells within the PAG was also found. Furthermore, chronic IH was associated with increased glutamate receptor subunit GluN2B expression in the spinal cord.

Conclusions

These findings collectively suggest that neuronal inflammation and alterations in synaptic plasticity are central to the development of hyperalgesia in IH-exposed mice. Our results provide crucial mechanistic insights into how IH can induce heightened pain sensitivity and underscore the importance of early therapeutic intervention to address sensory complications in patients with chronic sleep apnoea.

Significance Statement

Our study is the first to demonstrate that increased glial cells and elevated NMDA GluN2B expression in the spinal cord and PAG may drive sleep-related IH-induced hyperalgesia, linking sleep apnea to heightened pain sensitivity. Targeting central nervous system inflammation or GluN2B receptors could be crucial for mitigating the health impacts of sleep apnea.

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睡眠呼吸暂停小鼠模型中间歇性缺氧触发神经胶质细胞激活、GluN2B受体上调和痛觉过敏

睡眠呼吸暂停是一种破坏生理稳态，导致神经元功能障碍并引发一系列神经生物学效应的疾病。患有睡眠呼吸暂停和相关障碍的个体可能会经历更多的焦虑和感觉功能障碍，尽管这些现象尚未得到充分研究。方法采用小鼠模型研究睡眠呼吸暂停诱导的间歇性缺氧（IH）对小鼠感觉功能的影响及慢性IH的机制。小鼠暴露于慢性IH 10天，以评估脊髓和导水管周围灰质（PAG）等关键区域的神经元炎症和神经元可塑性变化，以了解IH如何改变感觉传导途径。结果我们的分析显示，暴露于IH的小鼠，下脊髓背角和腹角的星形胶质细胞和小胶质细胞显著上调，并伴有细胞因子（IL-1β和TNF-α）水平升高，提示炎症反应。此外，还发现PAG内星形胶质细胞显著增加。此外，慢性IH与脊髓中谷氨酸受体亚基GluN2B表达增加有关。这些发现共同表明，神经元炎症和突触可塑性的改变是ih暴露小鼠痛觉过敏发展的核心。我们的研究结果为IH如何诱导疼痛敏感性升高提供了重要的机制见解，并强调了早期治疗干预解决慢性睡眠呼吸暂停患者感觉并发症的重要性。我们的研究首次证明，脊髓和PAG中神经胶质细胞的增加和NMDA GluN2B表达的升高可能驱动睡眠相关的ih诱导的痛觉过敏，将睡眠呼吸暂停与疼痛敏感性升高联系起来。靶向中枢神经系统炎症或GluN2B受体对于减轻睡眠呼吸暂停对健康的影响至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Pain 医学-临床神经学

CiteScore

7.50

自引率

5.60%

发文量

163

审稿时长

4-8 weeks

期刊介绍： European Journal of Pain (EJP) publishes clinical and basic science research papers relevant to all aspects of pain and its management, including specialties such as anaesthesia, dentistry, neurology and neurosurgery, orthopaedics, palliative care, pharmacology, physiology, psychiatry, psychology and rehabilitation; socio-economic aspects of pain are also covered. Regular sections in the journal are as follows: • Editorials and Commentaries • Position Papers and Guidelines • Reviews • Original Articles • Letters • Bookshelf The journal particularly welcomes clinical trials, which are published on an occasional basis. Research articles are published under the following subject headings: • Neurobiology • Neurology • Experimental Pharmacology • Clinical Pharmacology • Psychology • Behavioural Therapy • Epidemiology • Cancer Pain • Acute Pain • Clinical Trials.