Baudat Mathilde, Joosten Elbert A J, Simons Sinno H P, van den Hove Daniël L A, Riemens Renzo J M
Department of Anesthesiology and Pain Management, Maastricht University Medical Centre+, Maastricht, the Netherlands.
Department of Translational Neuroscience, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, the Netherlands.
Pediatr Res. 2025 Jan 30. doi: 10.1038/s41390-025-03892-7.
Repetitive neonatal painful procedures experienced in the neonatal intensive care unit (NICU) are known to alter the development of the nociceptive system and have long-lasting consequences. Recent evidence indicates that NICU stay affects the methylation of the opioid receptor mu 1 encoding gene (Mor-1). Additionally, a preclinical model of neonatal procedural pain established lower adult post-operative MOR-1 levels in the spinal cord. Thus, we hypothesized that neonatal procedural pain increases the DNA methylation status of Mor-1 in the spinal cord and dorsal root ganglia (DRGs).
To this end, repetitive neonatal procedural pain was induced in animals, during the first postnatal week, a period equivalent to preterm human brain development. On postnatal day 10 methylation of Mor-1 promotor was assessed in the spinal cord and the DRG using bisulfite pyrosequencing.
Our findings demonstrated that neonatal procedural pain increased spinal cord Mor-1 promotor DNA methylation in the ipsilateral side as compared to the contralateral side, an effect that was not observed in the control animals, nor in the DRG.
This study is the first to highlight a localized and noxious-stimuli-dependent effect of repetitive neonatal procedural pain on Mor-1 promotor methylation and emphasizes the need to explore the effects of repetitive neonatal procedural pain on the epigenome.
This study reveals that repetitive neonatal procedural pain is associated with increased DNA methylation of the Mor-1 promoter in the spinal cord of neonatal rats. This is the first study to identify an effect of neonatal procedural pain on DNA methylation, emphasizing the critical need for further investigation into the epigenetic consequences of neonatal procedural pain. These insights could lead to better management and treatment strategies to mitigate the long-term impacts of early pain exposure on neurodevelopment and behavior.
已知新生儿重症监护病房（NICU）中经历的重复性新生儿疼痛操作会改变伤害性感受系统的发育并产生长期后果。最近的证据表明，在NICU的住院经历会影响阿片受体μ1编码基因（Mor-1）的甲基化。此外，新生儿程序性疼痛的临床前模型显示成年后脊髓中MOR-1水平降低。因此，我们推测新生儿程序性疼痛会增加脊髓和背根神经节（DRG）中Mor-1的DNA甲基化状态。
为此，在出生后的第一周（相当于人类早产儿脑发育阶段）对动物诱导产生重复性新生儿程序性疼痛。在出生后第10天，使用亚硫酸氢盐焦磷酸测序法评估脊髓和DRG中Mor-1启动子的甲基化情况。
我们的研究结果表明，与对侧相比，新生儿程序性疼痛增加了同侧脊髓Mor-1启动子的DNA甲基化，在对照动物和DRG中未观察到这种效应。
本研究首次强调了重复性新生儿程序性疼痛对Mor-1启动子甲基化的局部和有害刺激依赖性影响，并强调有必要探索重复性新生儿程序性疼痛对表观基因组的影响。
本研究表明，重复性新生儿程序性疼痛与新生大鼠脊髓中Mor-1启动子的DNA甲基化增加有关。这是第一项确定新生儿程序性疼痛对DNA甲基化有影响的研究，强调迫切需要进一步研究新生儿程序性疼痛的表观遗传后果。这些见解可能会带来更好的管理和治疗策略，以减轻早期疼痛暴露对神经发育和行为的长期影响。
