The Expression of Neuropeptides in Pulpitis: A Systematic Review and Meta-Analysis

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.

This systematic review and meta-analysis aimed to evaluate evidence for neuropeptide expression at post-transcriptional and post-translational levels in human teeth diagnosed with symptomatic irreversible pulpitis.

The review followed PRISMA guidelines and was registered on PROSPERO. Four databases (MEDLINE, Embase, Web of Science and Scopus) were searched for English-language studies investigating neuropeptide RNA or protein expression in human permanent teeth. Two reviewers independently performed study selection, data extraction and risk-of-bias assessment using the Quality Assessment Tool for In Vitro Studies (QUIN) tool, with conflicts resolved by a third reviewer. Meta-analysis was conducted using random- and fixed-effects models, with subgroup analyses by neuropeptide type and expression level. Studies lacking sufficient quantitative data were included in a narrative synthesis.

Fourteen observational studies involving 588 teeth met the inclusion criteria. Limited evidence of neuropeptide synthesis for calcitonin gene-related peptide (CGRP) in the pulp was identified. However, consistent post-translational 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-transcriptional CGRP upregulation. Vasoactive intestinal peptide expression showed inconsistent findings, and secretoneurin showed a trend of increase only. Meta-analysis demonstrated a large, pooled effect size (SMD 2.88, CI: 2.00-3.77) 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.

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-quality research integrating gene and protein analyses with standardised clinical diagnostics is needed to define their role in guiding vital pulp treatment decisions.

The study protocol was registered in the international prospective register of systematic reviews (PROSPERO) (CRD42024600828).