TRPV1-linked neuropeptide axes in periodontitis and peri-implantitis

Periodontitis and peri-implantitis are the two most prevalent destructive diseases encountered in clinical dentistry, both of which arise from complex interactions among microbial challenge, host immune responses, and bone metabolism. Although these conditions share similar clinical manifestations, accumulating evidence indicates that the peripheral nervous system plays fundamentally distinct roles in their pathogenesis. In this narrative review, a structured literature search was conducted across multiple databases to synthesize and weigh current evidence on neuro-osteo-immune regulation in oral tissues. This review summarizes the bidirectional regulatory functions of neuropeptide axes, particularly the transient receptor potential vanilloid 1-calcitonin gene-related peptide (TRPV1-CGRP) axis and substance P-neurokinin 1 receptor (SP-NK1R) axis, within the bone-immune microenvironment. Current evidence suggests that CGRP is frequently associated with protective effects, including the promotion of osteogenesis and M2 macrophage polarization through the cAMP/PKA/CREB signaling cascade, whereas SP is more commonly associated with neurogenic inflammation and osteoclast activation in inflammatory settings, although both axes exhibit context-dependent effects. Special emphasis is placed on the impaired neural innervation of peri-implant tissues resulting from the absence of the periodontal ligament, as well as on the disruptive effects of titanium particle-induced foreign body reactions on neuro-immune crosstalk. By comparing the structural differences in neuro-osteo-immune regulation between these two diseases, we propose that periodontitis retains a certain capacity for self-regulation through periodontal ligament-mediated neural feedback, whereas peri-implantitis may be more prone to progressing toward chronic inflammation and bone destruction, potentially because of reduced neural input and persistent foreign body-related responses; however, this interpretation remains a conceptual model that requires direct validation in human disease. Finally, we discuss stage-specific therapeutic strategies targeting neuropeptide receptors and the prospective application of biomimetic implant coatings with neuromodulatory properties, aiming to provide a theoretical framework for future precision interventions in oral inflammatory diseases based on the neuro-osteo-immune axis.