From tooth pain to trigeminal sensitization: translational models, experimental readouts, and mechanism-guided therapeutic opportunities in odontogenic and headache-related orofacial pain.

Odontogenic pain is one of the most intense forms of orofacial pain, yet durable mechanism-directed therapies remain limited. Traditionally, tooth pain has been framed as a local consequence of pulpal, dentinal, periodontal, or periapical disease. However, contemporary orofacial pain and headache frameworks increasingly position dental pain within a broader trigeminal pain network, where nociceptive input from the teeth and surrounding tissues may contribute to referred facial pain, headache-related orofacial pain overlap, and trigeminal sensitization. In this review, we synthesize odontogenic pain as a clinically accessible model for studying peripheral-to-central trigeminal pain mechanisms. To align the review questions, scope, and content, the review is structured around 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. We emphasize the hot tooth phenotype, most commonly associated with symptomatic irreversible pulpitis, as a translational state in which severe peripheral inflammation, tissue acidosis, ion-channel remodeling, local anesthetic difficulty, neuroimmune activation, and central amplification converge. We summarize key molecular and circuit-level mechanisms, including inflammatory mediator release, ion-channel and receptor pathways related to thermal, acid, purinergic, sodium, calcium, mechanosensitive, and G protein-coupled signaling, trigeminal ganglion plasticity, satellite glial activation, calcitonin gene-related peptide signaling, trigeminocervical convergence, and central sensitization. We also discuss how preclinical models and experimental readouts can be aligned with specific clinical phenotypes, including five clinical phenotype domains: dentin hypersensitivity; acute pulpitis; the hot tooth phenotype as the index severe inflammatory pulpitis state; persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain; and headache-related orofacial pain overlap. By linking clinical phenotypes, mechanistic models, experimental readouts, biomarkers, target engagement, therapeutic strategies, and trial-design considerations, this framework may help bridge the gap between preclinical pain research and clinical application. Reframing odontogenic pain as a biologically informative trigeminal pain state may support the development of biomarker-guided, mechanism-informed, and more durable analgesic strategies for refractory dental and headache-related orofacial pain. Importantly, persistent or refractory odontogenic and headache-related orofacial pain is shaped not only by peripheral and central neurobiological mechanisms but also by patient-level contextual contributors such as sleep disruption, stress, prior pain and treatment experience, and affective-motivational processing, which help explain why patients with comparable dental findings differ in pain intensity, disability, and treatment response.