Circadian disruption upon painful peripheral nerve injury in mice: Temporal effects on transcriptome in pain-regulating sensory tissues

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease Pub Date : 2025-05-03 DOI:10.1016/j.nbd.2025.106934

Wenjing Dai , Manqing Wen , Eija Kalso , Vinko Palada

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Abstract

Background

Neuropathic pain (NP) resulting from nerve damage shows diurnal fluctuation of intensity in patients, indicating circadian regulation. However, mechanisms linking NP and circadian regulation remain unclear. This study aimed to investigate time-dependent transcriptomic changes during a 24-hour period using a spared nerve injury (SNI) mouse model of NP.

Methods

Pain-related behaviours were assessed at baseline and on days 7, 14, and 21 after SNI and control sham surgeries in C57BL/6JRJ mice. Spinal cord (SC) and periaqueductal gray (PAG) were collected 4-hourly over 24 h upon completion of behavioural testing.

Results

RNA sequencing revealed 111 up- and 21 downregulated differentially expressed genes (DEGs) in the SC, and 35 up- and 33 downregulated DEGs in the PAG, across all six time points. The large majority of DEGs, 245 in the SC and 191 in the PAG, are involved in regulation of immunity. Among the top expressed genes, five DEGs in the SC, Atf3, Anxa10, Gpr151, Cxcl10, Sprr1a, and two DEGs in the PAG, Igf2 and Wnt6, were previously reported to regulate pain. Circadian analysis using CircaCompare identified 383 SC transcripts and 261 PAG transcripts with altered rhythmicity. Variability of gene expression during circadian day was increased in the SC and decreased in the PAG from the SNI mice.

Conclusion

These findings suggest that NP disrupts the circadian expression of rhythmic transcripts in the SC and PAG, potentially revealing new targets for chronotherapy of NP.

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小鼠疼痛周围神经损伤的昼夜节律中断：疼痛调节感觉组织转录组的时间效应

背景：神经损伤引起的神经性疼痛（NP）在患者中表现出昼夜强度波动，表明昼夜节律调节。然而，NP与昼夜节律调节的联系机制尚不清楚。本研究旨在研究NP小鼠模型在24小时内的时间依赖性转录组变化。方法观察C57BL/6JRJ小鼠在SNI和对照假手术后的基线和第7、14、21天的西班牙相关行为。脊髓（SC）和导水管周围灰质（PAG）在行为测试完成后24小时内每4小时采集一次。结果rna测序显示，在所有6个时间点，SC中有111个差异表达基因（deg）上调，21个差异表达基因（deg）下调，PAG中有35个差异表达基因（deg）上调，33个差异表达基因（deg）下调。绝大多数deg （SC 245个，PAG 191个）参与免疫调节。在表达最多的基因中，SC中的5个deg （Atf3、Anxa10、Gpr151、Cxcl10、Sprr1a）和PAG中的2个deg （Igf2和Wnt6）先前被报道调节疼痛。使用circacomare进行昼夜节律分析，鉴定出383个SC转录本和261个PAG转录本节律性改变。在SNI小鼠的SC中，昼夜节律期间基因表达的变异性增加，而在PAG中减少。这些发现表明NP破坏SC和PAG中节律转录物的昼夜表达，可能揭示NP时间治疗的新靶点。

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

Neurobiology of Disease 医学-神经科学

CiteScore

11.20

自引率

3.30%

发文量

270

审稿时长

76 days

期刊介绍： Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.