The Role of Neuropeptide Y in Dental Pulp: Balancing Neurogenic Inflammation and Pain Modulation

BACKGROUND: Dental pulp is a densely innervated, low-compliance tissue in which neurogenic inflammation can rapidly escalate into oedema, raised intrapulpal pressure, microvascular compromise, and pain. While Substance P (SP) and Calcitonin gene-related peptide (CGRP) are well-established drivers of pulp vasodilation, the Neuroopeptide Y (NPY) endogenous counter-regulatory mechanism remain comparatively under-explored. OBJECTIVES: To critically synthesise current evidence on NPY in dental pulp biology, focusing on its roles in neurogenic inflammation, neuroimmune modulation, vascular control and nociceptive signalling, and to evaluate whether NPY release represents a physiologically meaningful intrinsic analgesic mechanism during restorative-procedure-related pulpal stress and dentine hypersensitivity. METHODS: A PRISMA-guided literature search was conducted in PubMed, Web of Science and Scopus from inception to February 2026, supplemented by grey literature and reference screening. Experimental (in vitro/in vivo/ex vivo), human and animal tissue-based studies, and relevant reviews reporting molecular, cellular, or functional data on NPY and its receptors (particularly Y1/Y2) in the context of pulp inflammation and pain were included. Study selection and data extraction were performed independently by two reviewers. RESULTS: Ninety-two studies met inclusion criteria for narrative synthesis. Across models, NPY emerged as a master homeostatic regulator acting via Gi/Go-coupled receptors to oppose sensory neuropeptide-driven excitation. Y1 signalling, expressed in vascular smooth muscle and multiple pulp cell populations, mediates vasoconstriction and exerts antinociceptive effects partly through inhibition of TRPV1-expressing nociceptors and suppression of CGRP release. In other tissues, Y2 signalling functions predominantly presynaptically to limit SP/CGRP spillover, establishing a negative-feedback 'brake' on neurogenic escalation, suggesting it may have a role in dental pulp as well. Stage-dependent changes in NPY/Y1 expression in pulp of carious teeth indicate an early protective programme that may fail as tissue damage and denervation advance. Mechanistic and clinical data converge on a model in which pulp outcomes reflect the balance between excitatory (SP/CGRP) and NPY-mediated inhibitory tone. CONCLUSION: NPY signalling constitutes a potential counter-regulatory axis integrating vascular control, neuroimmune responses, and pain modulation in dental pulp. NPY may function as an intrinsic analgesic mechanism that limits procedure- and caries-associated neurogenic inflammation and dentine hypersensitivity.