Post-traumatic trigeminal neuropathy (PTTN) is a kind of chronic pain caused by damage to the trigeminal nerve. Previous study reported that pretreatment with neutralizing antibody against high mobility group box-1 (HMGB1) prevented the onset of PTTN in mice a distal infraorbital nerve chronic constriction injury (dIoN-CCI). However, mechanisms how HMGB1 evokes the PTTN is unclear. Hence, the current study investigated whether HMGB1 evokes the PTTN through the activation of specific receptor.

Under anesthesia, silk sutures were tied loosely around the dIoN in male mice. Nociceptive-like behaviors were evaluated by measurement of face grooming time. Microglial activity in spinal trigeminal nucleus caudalis (Sp5c) was determined by immunohistochemistry. The inhibitors of Toll-like receptor 4 (TLR4) or receptor for advanced glycation end products (RAGE) were perineurally treated after dIoN-CCI.

The increased facial grooming time in dIoN-CCI mice was attenuated by pretreatment with RAGE inhibitor (FPS-ZM1), but not TLR4 inhibitor (TAK242). Additionally, the FPS-ZM1 treatment inhibited microglial activation in Sp5c. These data suggest that RAGE plays a crucial role to develop the PTTN after the nerve injury. Thus, the RAGE could be a novel therapeutic target for inhibiting the onset of PTTN.