Trigeminal neuralgia: from clinical challenges to molecular insights.

Trigeminal neuralgia (TN) is a paroxysmal, recurrent, electric shock‑ or knife‑like severe pain localized to the sensory distribution of the trigeminal nerve branches in the face. Often referred to as "the most painful affliction known to humankind". First-line drugs carbamazepine and oxcarbazepine are associated with long-term side effects and diminishing efficacy, highlighting an urgent need for new therapeutic strategies. This review systematically summarizes the current progress in TN animal models (ranging from chronic constriction and inflammatory models to genetically engineered models), the multi-brain-region interactive pain transmission circuitry, molecular targets (voltage-gated sodium/calcium/potassium channels, TRP channels, chemokines, and epigenetic regulators), and drug development. Current treatments primarily rely on ion channel modulators, while emerging strategies involve Nav1.7/Cav3.2 inhibitors, CGRP antibodies, NRF2 activators, and botulinum toxin. Future efforts should focus on establishing more clinically translational precision models, dissecting the spatiotemporal dynamics of neural circuits, promoting multi-target combination therapies based on molecular subtyping, and accelerating the transition from symptomatic control to curative treatment.