{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T22:49:36Z","timestamp":1784933376682,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Developmental Neurobiology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Neonatal procedural pain experienced in the neonatal intensive care unit can lead to long\u2010lasting remodeling of the central nervous system and, in particular, of the spinal nociceptive network. Preclinical studies indicate a disrupted inhibitory versus excitatory balance in the spinal cord due to reduced \u03b3\u2010aminobutyric acid (GABA) ergic neurotransmission. During neonatal development a GABAergic shift occurs, which is regulated by the potassium\u2010chloride co\u2010transporter 2 (KCC2) and its oxytocin receptor (OXTR)\u2010dependent phosphorylation at the serine 940 residue (pKCC2). As DNA methylation of\n                    <jats:italic>Oxtr<\/jats:italic>\n                    is sensitive to early life adversity, such as neonatal procedural pain, we hypothesized that neonatal procedural pain reduces\n                    <jats:italic>Oxtr<\/jats:italic>\n                    methylation in the lumbar spinal cord and subsequently prevents the developmental increase in KCC2 and pKCC2. Using a rat model of repetitive neonatal procedural pain, four needle pricks were applied to the left hind paw every day from postnatal day (P)0 to P7. Spinal cord samples were collected at P0 and P10 to assess the levels of KCC2 and pKCC2 via Western blot analysis. Additionally, spinal\n                    <jats:italic>Oxtr<\/jats:italic>\n                    methylation was quantified using bisulfite pyrosequencing. The results indicated that neonatal procedural pain downregulates spinal pKCC2 levels, while KCC2 levels remain unchanged. These findings suggest a disrupted KCC2\u2010dependent chloride outflow and support the hypothesis that neonatal procedural pain disrupts the GABAergic shift. A developmental decrease in pKCC2\/KCC2 levels was also observed in the ipsilateral spinal cord of P10 animals, indicating the involvement of other post\u2010translational mechanisms in the developmental regulation of spinal KCC2. Methylation of the\n                    <jats:italic>Oxtr<\/jats:italic>\n                    does not seem to be related to the disturbed GABAergic shift, given that no significant changes in\n                    <jats:italic>Oxtr<\/jats:italic>\n                    promoter methylation were detected. Overall, this study demonstrates that neonatal procedural pain disrupts spinal KCC2 phosphorylation and supports the hypothesis that neonatal procedural pain alters the GABAergic shift in the spinal cord.\n                  <\/jats:p>","DOI":"10.1002\/dneu.22993","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T06:28:08Z","timestamp":1754980088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neonatal Procedural Pain Disrupts Phosphorylation of KCC2 in the Spinal Cord"],"prefix":"10.1002","volume":"85","author":[{"given":"Mathilde","family":"Baudat","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Management Maastricht University Medical Centre+  Maastricht the Netherlands"},{"name":"Department of Translational Neuroscience, Mental Health and Neuroscience Research Institute Maastricht University  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elbert A. J","family":"Joosten","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Management Maastricht University Medical Centre+  Maastricht the Netherlands"},{"name":"Department of Translational Neuroscience, Mental Health and Neuroscience Research Institute Maastricht University  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinno H. P.","family":"Simons","sequence":"additional","affiliation":[{"name":"Department of Neonatal and Pediatric Intensive Care, Division of Neonatology Erasmus University Medical Centre Rotterdam\u2010Sophia Children Hospital  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dani\u00ebl L. A. van den","family":"Hove","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute Maastricht University  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo J. M.","family":"Riemens","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute Maastricht University  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2007.05.004"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.09.028"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/dev.22478"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2015.05.022"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn920"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00254"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-4-19"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.14324"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.300.1.60"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpain.2022.872587"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/dev.22210"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jdn.10185"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.09.025"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.09.143"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1674-14.2015"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00341-5"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2020.12.010"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20020329"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2005.04529.x"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2011.11.011"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-3806(94)90098-1"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1943-23.2023"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22047"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2018.11.016"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2806"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705053200"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.03.013"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2013.10.057"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3547-15.2016"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3585-14.2015"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2023.1296527"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2017_14"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.5863\/1551-6776-22.3.207"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.08.035"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1946"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(97)00084-3"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1133212"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/scan\/nsw051"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-020-01353-x"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2019.05.004"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001201"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-019-0420-x"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22583"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.855"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaw9315"}],"container-title":["Developmental 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