Multidimensional mechanisms of the trigeminal–limbic axis underlying TMD–anxiety comorbidity—a narrative review

Temporomandibular disorder (TMD) comprises a heterogeneous group of pain-related and intra-articular conditions affecting the temporomandibular joint and masticatory system and are frequently accompanied by anxiety symptoms. Clinical research supports the association among painful TMD, psychological distress, central sensitization and alterations in the pain-emotion network, but a disease circuit defined by projection has not yet been established. Accordingly, this narrative review distinguishes TMD-direct evidence from mechanistic evidence derived from other pain and threat models and from hypotheses requiring TMD-specific validation. Recent studies using optogenetics, transcriptomic profiling, neural tracing, and in vivo calcium imaging have identified cell-type-specific encoding, neuroimmune-mediated synaptic remodeling, and adaptations in long-range circuits in models of chronic pain and anxiety. These findings have led to predictions of the mechanism of TMD, but should not be interpreted as direct evidence of the pathogenesis of TMD. The trigeminal–limbic axis is defined here as a set of candidate projection-defined pathways through which temporomandibular nociceptive input may influence affective, autonomic, and motor outputs. Across non-TMD experimental models, the trigeminal ganglion (TG)-caudal subnucleus of the spinal trigeminal nucleus (Vc)-lateral parabrachial nucleus (PBN) calcitonin gene-related peptide-positive (CGRP⁺)-central amygdala (CeA) pathway is supported as a biologically plausible candidate, alongside trigemino–thalamo–cortical processing and other potential routes conveying information to the amygdala. Whether the combination of the periaqueductal gray (PAG)- rostral ventromedial medulla (RVM)-Vc axis driven by CeA and the brainstem motor circuit constitutes a functional closed loop remains a hypothesis that can be directly experimentally verified. Rather than treating CeA as a single dominant node, this assessment includes the amygdala microcircuit, neuroimmune signaling, hypothalamic-pituitary-adrenal (HPA) axis activity and the descending regulatory system. Looking ahead, this review outlines a falsifiable experimental design and a preliminary biomarker framework, both of which will depend on mechanism studies in human subjects and prospective clinical validation.