Blencowe, H. et al. Born too soon: the global epidemiology of 15 million preterm births. Reprod. Health 10, 1–14 (2013).

Article  Google Scholar 

Tielsch, J. M. Global incidence of preterm birth. : Low. -Birthweight Baby: Born Too Soon or. Too Small. Karger Publishers 81, 9–15 (2015).

Google Scholar 

Gamber, R. A., Blonsky, H., Mcdowell, M. & Lakshminrusimha, S. Declining birth rates, increasing maternal age and neonatal intensive care unit admissions. J. Perinatol. 44, 203–208 (2024).

Article  PubMed  Google Scholar 

Carbajal, R. et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 300, 60–70 (2008).

Article  CAS  PubMed  Google Scholar 

Cruz, M. D., Fernandes, A. M. & Oliveira, C. R. Epidemiology of painful procedures performed in neonates: a systematic review of observational studies. Eur. J. Pain. 20, 489–498 (2016).

Article  CAS  PubMed  Google Scholar 

Grunau, R.E. Neonatal pain in very preterm infants: long-term effects on brain, neurodevelopment and pain reactivity. Rambam Maimonides Med. J, 4, e0025 (2013).

de Kort, A. R., Joosten, E. A., Patijn, J., Tibboel, D. & van den Hoogen, N. J. Anatomical changes in descending serotonergic projections from the rostral ventromedial medulla to the spinal dorsal horn following repetitive neonatal painful procedures. Int. J. Developmental Neurosci. 82, 361–371 (2022).

Article  Google Scholar 

van den Hoogen, N.J. et al. Developmental neurobiology as a guide for pharmacological management of pain in neonates. Semin Fetal Neonatal Med. 24. (2019).

LaPrairie, J.L., Murphy, A.Z. Neonatal injury alters adult pain sensitivity by increasing opioid tone in the periaqueductal gray. Front Behav Neurosci. 3. (2009).

Kwoky, C. H. T., Devonshire, I. M., Bennett, A. J. & Hathway, G. J. Postnatal maturation of endogenous opioid systems within the periaqueductal grey and spinal dorsal horn of the rat. Pain 155, 168–178 (2014).

Article  Google Scholar 

Hathway, G. J., Vega-Avelaira, D. & Fitzgerald, M. A critical period in the supraspinal control of pain: opioid-dependent changes in brainstem rostroventral medulla function in preadolescence. Pain 153, 775–783 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Attali, B., Saya, D. & Vogel, Z. Pre-and postnatal development of opiate receptor subtypes in rat spinal cord. Dev. Brain Res. 53, 97–102 (1990).

Article  CAS  Google Scholar 

Beland, B. & Fitzgerald, M. Mu-and delta-opioid receptors are downregulated in the largest diameter primary sensory neurons during postnatal development in rats. Pain 90, 143–150 (2001).

Article  CAS  PubMed  Google Scholar 

Nandi, R. et al. The functional expression of mu opioid receptors on sensory neurons is developmentally regulated; morphine analgesia is less selective in the neonate. Pain 111, 38–50 (2001).

Article  Google Scholar 

Arvidsson, U. et al. Distribution and targeting of a p.-opioid receptor (MORI) in brain and spinal cord. J. Neurosci. 75, 3328–3341 (1994).

Google Scholar 

Terman, G. W., Eastman, C. L. & Chavkin, C. Mu opiates inhibit long-term potentiation induction in the spinal cord slice. J. Neurophysiol. 85, 485–494 (2001).

Article  CAS  PubMed  Google Scholar 

Kivell, B. M., Day, D. J., McDonald, F. J. & Miller, J. H. Developmental expression of μ and δ opioid receptors in the rat brainstem: Evidence for a postnatal switch in μ isoform expression. Dev. Brain Res. 148, 185–196 (2004).

Article  CAS  Google Scholar 

Rahman, W., Dashwood, M. R., Fitzgerald, M., Aynsley-Green, A. & Dickenson, A. H. Postnatal development of multiple opioid receptors in the spinal cord and development of spinal morphine analgesia. Dev. Brain Res. 108, 239–254 (1998).

Article  CAS  Google Scholar 

Fields, H. State-dependent opioid control of pain. Nat. Rev. Neurosci. 5, 565–575 (2004).

Article  CAS  PubMed  Google Scholar 

van den Hoogen, N. J., van Reij, R. R. I., Patijn, J., Tibboel, D. & Joosten, E. A. J. Adult spinal opioid receptor μ1 expression after incision is altered by early life repetitive tactile and noxious procedures in rats. Dev. Neurobiol. 78, 417–426 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Jirtle, R. L. & Skinner, M. K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet 8, 253–262 (2007).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kundakovic, M. & Jaric, I. The epigenetic link between prenatal adverse environments and neurodevelopmental disorders. Genes 8, 104 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Hwang, C. K. et al. Evidence of endogenous Mu opioid receptor regulation by epigenetic control of the promoters. Mol. Cell Biol. 27, 4720–4736 (2007).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cuitavi, J., Hipólito, L. & Canals, M. The life cycle of the Mu-opioid receptor. Trends Biochem Sci. 46, 315–328 (2021).

Article  CAS  PubMed  Google Scholar 

Van Dokkum, N. H. et al. Neonatal stress exposure and DNA methylation of stress-related and neurodevelopmentally relevant genes: An exploratory study. Early Hum. Dev. 186, 1058–1068 (2023).

Google Scholar 

Sun, N. et al. MeCP2 epigenetic silencing of Oprm1 gene in primary sensory neurons under neuropathic pain conditions. Front Neurosci. 15. (2021).

Sun, L. et al. Nerve injury–induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons. Pain 158, 1153–1165 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chidambaran, V. et al. Dna methylation at the mu-1 opioid receptor gene (OPRM1) promoter predicts preoperative, acute, and chronic postsurgical pain after spine fusion. Pharmgenomics Pers. Med 10, 157–168 (2017).

CAS  PubMed  PubMed Central  Google Scholar 

Romijna, H. J., Hofmana, M. A. & Gramsbergenb, A. At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? Early Hum. Dev. 26, 61–67 (1991).

Article  Google Scholar 

Workman, A. D., Charvet, C. J., Clancy, B., Darlington, R. B. & Finlay, B. L. Modeling transformations of neurodevelopmental sequences across mammalian species. J. Neurosci. 33, 7368–7383 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ohmura, Y. & Kuniyoshi, Y. A translational model to determine rodent’s age from human foetal age. Sci. Rep. 7, 17248 (2017).

Article  PubMed  PubMed Central  Google Scholar 

van den Hoogen, N. J., Patijn, J., Tibboe, D. & Joosten, E. A. Repetitive noxious stimuli during early development affect acute and long-term mechanical sensitivity in rats. Pediatr. Res 87, 26–31 (2020).

Article  PubMed  Google Scholar 

de Kort, A. R., Joosten, E. A., Patijn, J., Tibboel, D. & van den Hoogen, N. J. Neonatal procedural pain affects state, but not trait anxiety behavior in adult rats. Dev. Psychobiol. 63, e22210 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Knaepen, L. et al. Neonatal repetitive needle pricking: plasticity of the spinal nociceptive circuit and extended postoperative pain in later life. Dev. Neurobiol. 73, 85–97 (2013).

Article  PubMed  Google Scholar 

Heinke, B., Gingl, E. & Sandkühler, J. Multiple targets of-opioid receptor-mediated presynaptic inhibition at primary afferent A-and C-fibers. J. Neurosci. 31, 1313–1322 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lightbourn, A. V. Posttranscriptional regulation of Mu opioid receptor (MOR-1): Implications of alternative splicing in the neuropathogenesis of morphine tolerance. Literature review and research approach. J. Anest. Inten. Care Med 9, 555767 (2019).

Google Scholar 

Wei, L. N. & Loh, H. H. Transcriptional and epigenetic regulation of opioid receptor genes: Present and future. Annu Rev. Pharm. Toxicol. 51, 75–97 (2011).

Article  CAS  Google Scholar 

Talbot, J. N., Happe, H. K. & Murrin, C. L. Opioid receptor coupling to G i/o proteins increases during postnatal development in rat brain. J. Pharm. Exp. Ther. 314, 596–602 (2005).

Article  CAS  Google Scholar 

Moriarty, O. et al. Priming of adult