Neuroimmune alterations and nociceptive behavior in oral carcinogenesis in rats

Oral cancer pain is a frequent and debilitating symptom associated with tumor progression. Although neuronal mechanisms have been extensively studied, the role of immune and glial cells in the trigeminal nociceptive pathway remains poorly understood. In this study, male Wistar rats were exposed to 4-nitroquinoline-1-oxide for 8, 12, 16, or 20 wk. Mechanical allodynia was assessed using the von Frey test, and immunohistochemistry/immunofluorescence analyzed macrophage infiltration in the tongue and activation markers (nitrotyrosine, p-p38, glutamine synthetase, and Iba-1) in the trigeminal ganglion (TG) and spinal trigeminal subnucleus caudalis (Sp5C), focusing on animals with the highest nociceptive responses and macrophage infiltration. A reduction in mechanical thresholds was observed from Week 8, coinciding with histopathological alterations in the tongue. At 16 and 20 wk, Iba-1 immunoreactivity increased in the tongue and Sp5C, accompanied by morphological microglial changes, whereas nitrotyrosine and p-p38 expression were elevated in the TG. These findings indicate a temporal association between peripheral tissue changes, nociceptive behavior, and glial/immune activation in both central and peripheral trigeminal structures, suggesting that neuroimmune interactions may contribute to the development of oral cancer pain.