Dental nerves: a neglected mediator of pulpitis

Abstract

As one of the most densely innervated tissues, the dental pulp contains abundant nerve fibres, including sensory, sympathetic and parasympathetic nerve fibres. Studies in animal models and human patients with pulpitis have revealed distinct alterations in protein expression and histological appearance in all types of dental nerve fibres. Various molecules secreted by neurons, such as classical neurotransmitters, neuropeptides and amino acids, not only contribute to the induction, sensitization and maintenance of tooth pain, but also regulate non-neuronal cells, including fibroblasts, odontoblasts, immune cells and vascular endothelial cells. Dental nerves are particularly important for the microcirculatory and immune responses in pulpitis via their release of a variety of functional substances. Further, nerve fibres are found to be involved in dental soft and hard tissue repair. Thus, understanding how dental nerves participate in pulpitis could have important clinical ramifications for endodontic treatment. In this review, the roles of dental nerves in regulating pulpal inflammatory processes are highlighted and their implications for future research on this topic are discussed.

The role of inflammation modulation in dental pulp regeneration

“…Membrane-bound receptors for functional molecules from dental nerves are expressed on odontoblasts, fibroblasts, inflammatory cells and endothelial cells of capillaries, indicating a bidirectional cross-talks between these structures and nerve endings. Besides supporting the odontoblastic receptor theory of dentine sensitivity (Zhan et al, 2020), such intimate anatomical and functional interaction between pulpal nerve endings and other pulpal structures strongly suggests their intertwining functional relationship in all DP events, including inflammation and regeneration.…”

“…Progressing within the pulp, the sympathetic group, associated with the pulpal aspect of the odontoblastic layer, counteracts by an anti-inflammatory action. Such action includes the induction of anti-inflammatory macrophages by inhibition of cytokine IL-1a production, a bone-resorbing and a pro-inflammatory factor (Bletsa et al, 2004;Zhan et al, 2020). NGF, a neuropeptide involved in the regulation of growth, maintenance, proliferation and survival of pulpal neurons, is highly expressed at the caries invasion site (Mitsiadis et al, 2017).…”

“…Since macrophage modulation and polarisation play a crucial role in pulpal and periapical inflammation, it is intuitive to attempt DP regeneration by using macrophage-mobilising molecules to harness the inflammatory process for pulp regeneration. CGRP, a neuropeptide secreted by capsaicin-sensitive neurons in the DP, is known to promote proliferation of endothelial cells and pulpal fibroblasts and to increase DP vascular permeability (Bongenhielm et al, 1995;Zhan et al, 2020). CGRP is also a regulator of the immune response by acting as a signalling molecule for the M2 anti-inflammatory macrophage phenotype (Caviedes-Bucheli et al, 2008).…”

“…Before tissue necrosis, prostaglandin-mediated pain impulses are manifested clinically as a pulp reaction through the transmission carried by sensory nerve endings that, along with the sympathetic nerve endings, also play a role in regulating the DP inflammatory process by neuropeptide secretion targeting membrane bound receptors located on different pulp structures (Zhan et al, 2020). Neuropeptides, such as substance P, stimulate the production of pro-inflammatory cytokines from human DP fibroblasts; while CGRP is associated with immunosuppression and increased expression of BMP-2, promoting dentineogenesis within the DP (Calland et al, 1997).…”

“…Yet, more importantly, tooth devitalisation eliminates the innate immune and repair responses of a vital pulp (Farges et al, 2015;Hahn and Liewehr, 2007). This inflammationmodulated immune response, orchestrated by pulp fibroblasts, odontoblasts, endothelial cells and even nerve fibres (Zhan et al, 2020), plays a key role in fighting against caries invasion as well as secretion of tertiary and reparative dentine (Farges et al, 2015).…”