Preventive effect of RAGE antagonists on distal infraorbital nerve injury-induced pain behaviors of male and female mice

Post-traumatic trigeminal neuropathy (PTTN) is a debilitating sensory disorder resulting from trigeminal nerve damage for which effective therapies are lacking.Pretreatment with neutralizing antibodies against high mobility group box-1 (HMGB1), a damage-associated molecular pattern (DAMP), has shown promise in preventing PTTN development; however, the specific receptor mediating HMGB1-driven neuropathic pain in this context remains undefined. This study investigates the role of the receptor for advanced glycation end-products (RAGE), a key HMGB1 receptor, in PTTN pathogenesis using a distal infraorbital nerve chronic constriction injury (dIoN-CCI) model in both male and female mice.Following dIoN-CCI surgery, mice received two doses of a RAGE antagonist. Pain-like behavior was assessed by measuring facial grooming time, responses to cold stimulation, and mechanical sensitivity. The accumulation of macrophages, as well as the number and volume of microglia, were analyzed by immunohistochemical staining of the injured nerves and the spinal trigeminal nucleus caudalis (Sp5C). dIoN-CCI significantly increased pain-like behaviors in both sexes. Critically, prophylactic treatment with RAGE antagonists significantly attenuated all measured pain responses, regardless of sex. Furthermore, RAGE antagonism markedly reduced macrophage infiltration around the injured nerve and inhibited microglial activation in the Sp5C. These findings provide the first direct evidence that RAGE is crucial in PTTN pathogenesis driven by HMGB1 and demonstrate that RAGE antagonism effectively prevents PTTN development in both sexes. Consequently, early prophylactic treatment targeting RAGE presents a novel and promising strategy for patients at high risk of trigeminal nerve injury.