Review synthesizes odontogenic pain as translational model for trigeminal sensitization and mechanism-guided therapies

Odontogenic pain is a highly intense form of orofacial pain, yet effective mechanism-directed therapies remain scarce. Traditionally viewed as a local consequence of pulpal or periodontal disease, contemporary frameworks increasingly integrate dental pain within a broader trigeminal pain network. This shift recognizes that nociceptive input from teeth can contribute to referred facial pain, headache overlap, and trigeminal sensitization, highlighting a critical gap in understanding and treating its systemic implications.

This review synthesizes current understanding of odontogenic pain as a clinically accessible model for studying peripheral-to-central trigeminal pain mechanisms. The analysis is structured across five linked domains: clinically relevant phenotypes, peripheral-to-central mechanisms, phenotype-matched models and readouts, biomarker-based target engagement, and mechanism-guided therapeutic and trial-design strategies. It specifically emphasizes the 'hot tooth' phenotype, most commonly associated with symptomatic irreversible pulpitis, as a key translational state.

The review identifies key molecular and circuit-level mechanisms driving trigeminal sensitization, including inflammatory mediator release, ion-channel and receptor pathways related to thermal, acid, purinergic, sodium, calcium, mechanosensitive, and G protein-coupled signaling, and neuroimmune activation. It highlights trigeminal ganglion plasticity, satellite glial activation, calcitonin gene-related peptide signaling, trigeminocervical convergence, and central sensitization as critical processes.

The 'hot tooth' phenotype, linked to symptomatic irreversible pulpitis, is emphasized as a translational state where severe peripheral inflammation, tissue acidosis, ion-channel remodeling, local anesthetic difficulty, neuroimmune activation, and central amplification converge. The authors discuss aligning preclinical models and experimental readouts with five clinical phenotype domains: dentin hypersensitivity, acute pulpitis, the hot tooth phenotype as the index severe inflammatory pulpitis state, and persistent dentoalveolar pain.