Innervation Changes in Apical Periodontitis and its Correlation with Preoperative Symptoms

Previous anatomical studies have demonstrated the cellular composition of apical periodontitis (AP) lesions, primarily focusing on immune cells. Only recently has the innervation of an apical lesion been reported, but evidence regarding the quantity and quality of neural innervation in AP lesions remains largely unknown. Importantly, periapical innervation has been shown to modulate cellular response in AP, and the voltage-gated sodium channels Nav1.8, a marker of nociceptors, and Nav1.9 have been associated with various pain-related conditions. This study aimed to quantify sensory innervation and evaluate the expression of Nav1.8 and Nav1.9 in symptomatic vs asymptomatic AP.

Soft tissue biopsy samples (n = 20) were collected during endodontic microsurgery. Samples underwent protein extraction and immunohistochemistry. Enzyme-linked immunosorbent assay was used to quantify β-tubulin III Nav1.8 and Nav1.9. Immunoreactivity for calcitonin gene-related peptide, neurofilament heavy, PGP9.5, and Nav1.8 was analyzed using confocal microscopy. Data were analyzed using the Mann-Whitney U test with significance set at P < .05.

Symptomatic lesions exhibited an approximately 6-fold increase in innervation density (410.6 ± 359.2 vs 63.4 ± 75.7 pg/μg) and significantly higher Nav1.8 (10.3 ± 10.3 vs 2.97 ± 2.5 pg/μg) and Nav1.9 (9.5 ± 8.5 vs 42.5 ± 39.6 pg/μg) expression compared to asymptomatic lesions (P < .05). Neuronal fibers were identified by the co-localization of neurofilament heavy and PGP9.5 immunoreactivity, revealing a higher density of innervation in apical lesions from symptomatic cases. Notably, the majority of these fibers exhibited strong Nav1.8 expression, indicating a predominance of nociceptive innervation within these lesions.

This study provides novel evidence of increased sensory innervation and upregulation of Nav1.8 and Nav1.9 in symptomatic AP. These neural changes may contribute to pain mechanisms in AP and challenges in achieving local anesthesia.