{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:09:13Z","timestamp":1788944953521,"version":"build-2803163510"},"reference-count":75,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000297","name":"Royal College of Surgeons of England","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000297","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int Endodontic J"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neuropeptides play key roles in the inflammatory, nociceptive and reparative processes of the dental pulp. Their upregulation has been frequently observed in inflamed pulps, suggesting potential diagnostic value supporting a role for neurogenic inflammation in symptomatic irreversible pulpitis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This systematic review and meta\u2010analysis aimed to evaluate evidence for neuropeptide expression at post\u2010transcriptional and post\u2010translational levels in human teeth diagnosed with symptomatic irreversible pulpitis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>The review followed PRISMA guidelines and was registered on PROSPERO. Four databases (MEDLINE, Embase, Web of Science and Scopus) were searched for English\u2010language studies investigating neuropeptide RNA or protein expression in human permanent teeth. Two reviewers independently performed study selection, data extraction and risk\u2010of\u2010bias assessment using the Quality Assessment Tool for In\u00a0Vitro Studies (QUIN) tool, with conflicts resolved by a third reviewer. Meta\u2010analysis was conducted using random\u2010 and fixed\u2010effects models, with subgroup analyses by neuropeptide type and expression level. Studies lacking sufficient quantitative data were included in a narrative synthesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fourteen observational studies involving 588 teeth met the inclusion criteria. Limited evidence of neuropeptide synthesis for calcitonin gene\u2010related peptide (CGRP) in the pulp was identified. However, consistent post\u2010translational increased expression of Substance P (SP), CGRP, neurokinin A and neuropeptide Y was observed in pulpitic teeth compared with controls. One study additionally demonstrated post\u2010transcriptional CGRP upregulation. Vasoactive intestinal peptide expression showed inconsistent findings, and secretoneurin showed a trend of increase only. Meta\u2010analysis demonstrated a large, pooled effect size (SMD 2.88, CI: 2.00\u20133.77) with significant subgroup effects and substantial heterogeneity. SP and CGRP showed the strongest and most consistent increases across studies. Risk of bias was predominantly medium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Neuropeptides are consistently elevated in symptomatic irreversible pulpitis, particularly **SP** and **CGRP**, and may represent candidate biomarkers of pulpal inflammation. Current evidence suggests expression occurs predominantly via neuronal secretion rather than local synthesis. Despite consistent associations with pulpal inflammation, substantial heterogeneity, moderate study quality and the absence of diagnostic accuracy studies mean that their clinical utility remains uncertain. Further high\u2010quality research integrating gene and protein analyses with standardised clinical diagnostics is needed to define their role in guiding vital pulp treatment decisions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trail Registration<\/jats:title>\n                    <jats:p>The study protocol was registered in the international prospective register of systematic reviews (PROSPERO) (CRD42024600828)<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iej.70267","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:45:38Z","timestamp":1788943538000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Expression of Neuropeptides in Pulpitis: A Systematic Review and Meta\u2010Analysis"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4601-8897","authenticated-orcid":false,"given":"N.","family":"Watson","sequence":"first","affiliation":[{"name":"School of Pharmacy, Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0462-7463","authenticated-orcid":false,"given":"D.","family":"Edwards","sequence":"additional","affiliation":[{"name":"School of Dental Sciences, Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5983-964X","authenticated-orcid":false,"given":"Q.","family":"Vuong","sequence":"additional","affiliation":[{"name":"School of Psychology, Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Obara","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.4103\/jispcd.JISPCD_55_23","article-title":"Gingival Crevicular Fluid Levels of Neurokinin A and Substance P in Patients With Symptomatic Irreversible Pulpitis: A Systematic Review and Meta\u2010Analysis","volume":"13","author":"Abraham D.","year":"2023","journal-title":"J Int Soc Prev Community Dent"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1016\/j.joen.2020.07.013","article-title":"Comparison of Neurokinin A, Substance P, Interleukin 8, and Matrix Metalloproteinase\u20108 Changes in Pulp Tissue and Gingival Crevicular Fluid Samples of Healthy and Symptomatic Irreversible Pulpitis Teeth","volume":"46","author":"Akbal Dincer G.","year":"2020","journal-title":"Journal of Endodontics"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1111\/iej.13922","article-title":"Quantitative Analysis of Culturable Bacteria, Levels of Endotoxins, Inflammatory Mediators and Substance P in Teeth With Symptomatic Irreversible Pulpitis and in Teeth With Vital Normal Pulp Tissues","volume":"56","author":"Arruda\u2010Vasconcelos R.","year":"2023","journal-title":"International Endodontic Journal"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1046\/j.1365-2591.2002.00451.x","article-title":"Quantitative Analysis of Substance P, Neurokinin A and Calcitonin Gene\u2010Related Peptide in Pulp Tissue From Painful and Healthy Human Teeth","volume":"35","author":"Awawdeh L.","year":"2002","journal-title":"International Endodontic Journal"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1016\/0006-291X(80)90581-1","article-title":"Enhancement of Phagocytosis\u2013a Newly Found Activity of Substance P Residing in Its N\u2010Terminal Tetrapeptide Sequence","volume":"94","author":"Bar\u2010Shavit Z.","year":"1980","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0167-0115(95)00115-8","article-title":"Effects of Neuropeptides on Growth of Cultivated Rat Molar Pulp Fibroblasts","volume":"60","author":"Bongenhielm U.","year":"1995","journal-title":"Regulatory Peptides"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1097\/00004770-200304000-00009","article-title":"Tissue Levels of Immunoreactive Substance P Are Increased in Patients With Irreversible Pulpitis","volume":"29","author":"Bowles W. 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