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

Authors

Ezgi Cansu Firinciogullari, Kiran Alluri, Hanjun Wang, Sumit Yadav

Published in

The journal of headache and pain. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

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.

PMID:
42469638
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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