Differential Effects of Pregabalin and Morphine on the Sleep-Wake Cycle and Circadian Rhythms in Mice with Neuropathic Pain.

IF 9.1 1区医学 Q1 ANESTHESIOLOGY

Anesthesiology Pub Date : 2025-11-01 Epub Date: 2025-08-13 DOI:10.1097/ALN.0000000000005715

Wenjing Dai, Tommi Kilpeläinen, Manqing Wen, Chandreyee Roy, Anniina Lundén, Maija K Koskinen, Antti Pertovaara, Anni-Maija Talvio, Henna-Kaisa Wigren, Eija Kalso, Vinko Palada

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Abstract

Background: Neuropathic pain is commonly associated with disturbances in sleep architecture and circadian rhythms, leading to fragmented sleep, body temperature fluctuations, and altered locomotion. While pregabalin and morphine are frequently prescribed for neuropathic pain management, their effects on sleep and circadian regulation are poorly understood.

Methods: To identify the effects of spared nerve injury (SNI) on sleep architecture and circadian rhythms, male and female C57BL/6JRJ mice were implanted with wireless transmitters for continuous monitoring of electroencephalogram, electromyogram, locomotion, and body temperature. After baseline recordings, SNI was performed, and mechanical and dynamic allodynia was assessed on days 3, 7, and 14 after the surgeries. Pregabalin (11 mg/kg each day) or morphine (6 mg/kg each day) was administered continuously to male mice via intraperitoneal osmotic minipumps. Recordings were repeated on postoperative days 7 and 14.

Results: SNI significantly disrupted the sleep-wake cycle by reducing rapid eye movement (REM) sleep duration during the light phase (the habitual sleeping phase for mice) in both sexes and increasing wakefulness in females, without significantly affecting non-REM sleep. Additionally, SNI significantly impaired the circadian rhythmicity of locomotion and body temperature. Pregabalin, but not morphine, significantly restored REM sleep to presurgical levels and restored locomotor activity and body temperature rhythmicity more effectively than morphine. At the molecular level, SNI altered spinal cord circadian gene expression, which pregabalin significantly reversed, whereas morphine showed mixed effects. Furthermore, pregabalin increased sleep spindle occurrence during sleep stage transitions and enhanced the power spectra within the 3.5- to 5.5-Hz range during REM sleep. Morphine did not significantly alter either sleep architecture or microstructure in SNI mice.

Conclusions: Pregabalin, unlike morphine, restores SNI-disrupted sleep architecture, circadian rhythms, and spinal circadian gene expression.

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普瑞巴林和吗啡对神经性疼痛小鼠睡眠-觉醒周期和昼夜节律的差异影响。

背景：神经性疼痛通常与睡眠结构和昼夜节律紊乱有关，导致睡眠碎片化、体温波动和运动改变。虽然普瑞巴林和吗啡经常用于神经性疼痛治疗，但它们对睡眠和昼夜节律调节的影响尚不清楚。方法：为确定备用神经损伤（SNI）对睡眠结构和昼夜节律的影响，在雄性和雌性C57BL/6JRJ小鼠体内植入无线发射器，连续监测其脑电图（EEG）、肌电图（EMG）、运动和体温。基线记录后进行SNI，并在术后第3、7和14天评估机械和动态异常性疼痛。雄性小鼠经腹腔渗透微型泵连续给予普瑞巴林（11 mg/kg/day）或吗啡（6 mg/kg/day）。术后第7、14天重复记录。结果：SNI通过减少两性在光期（小鼠的习惯性睡眠阶段）的快速眼动（REM）睡眠持续时间和增加雌性的清醒程度，显著扰乱了睡眠-觉醒周期，但对非快速眼动睡眠没有明显影响。此外，SNI显著损害了运动和体温的昼夜节律性。普瑞巴林（而非吗啡）显著地将快速眼动睡眠恢复到手术前水平，并且比吗啡更有效地恢复运动活动和体温节律。在分子水平上，SNI改变脊髓昼夜节律基因表达，普瑞巴林显著逆转，而吗啡则表现出混合效应。此外，普瑞巴林增加了睡眠阶段转换期间睡眠纺锤体的发生，增强了快速眼动睡眠期间3.5-5.5 Hz范围内的功率谱。吗啡没有显著改变SNI小鼠的睡眠结构和微观结构。结论：与吗啡不同，普瑞巴林可以恢复sni中断的睡眠结构、昼夜节律和脊柱昼夜节律基因表达。

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

Anesthesiology 医学-麻醉学

CiteScore

10.40

自引率

5.70%

发文量

542

审稿时长

3-6 weeks

期刊介绍： With its establishment in 1940, Anesthesiology has emerged as a prominent leader in the field of anesthesiology, encompassing perioperative, critical care, and pain medicine. As the esteemed journal of the American Society of Anesthesiologists, Anesthesiology operates independently with full editorial freedom. Its distinguished Editorial Board, comprising renowned professionals from across the globe, drives the advancement of the specialty by presenting innovative research through immediate open access to select articles and granting free access to all published articles after a six-month period. Furthermore, Anesthesiology actively promotes groundbreaking studies through an influential press release program. The journal's unwavering commitment lies in the dissemination of exemplary work that enhances clinical practice and revolutionizes the practice of medicine within our discipline.