Repetitive neonatal pain increases spinal cord DNA methylation of the µ-opioid receptor

Mathilde Baudat; Elbert A.J. Joosten; Sinno H.P. Simons; Daniël L.A. van den Hove; Renzo J.M. Riemens

doi:10.1038/s41390-025-03892-7

Repetitive neonatal pain increases spinal cord DNA methylation of the µ-opioid receptor

Mathilde Baudat^*, Elbert A.J. Joosten, Sinno H.P. Simons, Daniël L.A. van den Hove, Renzo J.M. Riemens

^*Corresponding author for this work

Neonatal and Pediatric Intensive Care

Research output: Contribution to journal › Article › Academic › peer-review

1 Citation (Scopus)

Abstract

Background: 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). Methods: 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. Results: 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. Conclusion: 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.

Impact:

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.

Original language	English
Article number	17248
Pages (from-to)	1149-1154
Number of pages	6
Journal	Pediatric Research
Volume	98
Issue number	3
DOIs	https://doi.org/10.1038/s41390-025-03892-7
Publication status	Published - 30 Jan 2025

Bibliographical note

Publisher Copyright: © The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc 2025.

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10.1038/s41390-025-03892-7

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title = "Repetitive neonatal pain increases spinal cord DNA methylation of the µ-opioid receptor",

abstract = "Background: 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). Methods: 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. Results: 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. Conclusion: 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. Impact: 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.",

author = "Mathilde Baudat and Joosten, \{Elbert A.J.\} and Simons, \{Sinno H.P.\} and \{van den Hove\}, \{Dani{\"e}l L.A.\} and Riemens, \{Renzo J.M.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc 2025.",

year = "2025",

month = jan,

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doi = "10.1038/s41390-025-03892-7",

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T1 - Repetitive neonatal pain increases spinal cord DNA methylation of the µ-opioid receptor

AU - Baudat, Mathilde

AU - Joosten, Elbert A.J.

AU - Simons, Sinno H.P.

AU - van den Hove, Daniël L.A.

AU - Riemens, Renzo J.M.

N1 - Publisher Copyright: © The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc 2025.

PY - 2025/1/30

Y1 - 2025/1/30

N2 - Background: 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). Methods: 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. Results: 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. Conclusion: 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. Impact: 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.

AB - Background: 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). Methods: 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. Results: 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. Conclusion: 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. Impact: 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.

UR - https://www.scopus.com/pages/publications/85217204258

U2 - 10.1038/s41390-025-03892-7

DO - 10.1038/s41390-025-03892-7

M3 - Article

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AN - SCOPUS:85217204258

SN - 0031-3998

VL - 98

SP - 1149

EP - 1154

JO - Pediatric Research

JF - Pediatric Research

IS - 3

M1 - 17248

ER -

Repetitive neonatal pain increases spinal cord DNA methylation of the µ-opioid receptor

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