Involvement of interferon gamma signaling in spinal trigeminal caudal subnucleus astrocyte in orofacial neuropathic pain in rats with infraorbital nerve injury

Background: Trigeminal nerve injury causes orofacial pain that can interfere with activities of daily life. However, the underlying mechanism remains unknown, and the appropriate treatment has not been established yet. This study aimed to examine the involvement of interferon gamma (IFN-gamma) signaling in the spinal trigeminal caudal subnucleus (Vc) in orofacial neuropathic pain. Methods: Infraorbital nerve (ION) injury (IONI) was performed in rats by partial ION ligation. The head-withdrawal reflex threshold (HWT) to mechanical stimulation of the whisker pad skin was measured in IONI or sham rats, as well as following a continuous intracisterna magna administration of IFN-gamma and a mixture of IFN-gamma and fluorocitrate (inhibitor of astrocytes activation) in naive rats, or an IFN-gamma antagonist in IONI rats. The IFN-gamma receptor immunohistochemistry and IFN-gamma Western blotting were analyzed in the Vc after IONI or sham treatment. The glial fibrillary acid protein (GFAP) immunohistochemistry and Western blotting were also analyzed after administration of IFN-gamma and the mixture of IFN-gamma and fluorocitrate. Moreover, the change in single neuronal activity in the Vc was examined in the IONI, sham, and IONI group administered IFN-gamma antagonist. Results: The HWT decreased after IONI. The IFN-gamma and IFN-gamma receptor were upregulated after IONI, and the IFN-gamma receptor was expressed in Vc astrocytes. IFN-gamma administration decreased the HWT, whereas the mixture of IFN-gamma and fluorocitrate recovered the decrement of HWT. IFN-gamma administration upregulated GFAP expression, while the mixture of IFN-gamma and fluorocitrate recovered the upregulation of GFAP expression. IONI significantly enhanced the neuronal activity of the mechanical-evoked responses, and administration of an IFN-gamma antagonist significantly inhibited these enhancements. Conclusions: IFN-gamma signaling through the receptor in astrocytes is a key mechanism underlying orofacial neuropathic pain associated with trigeminal nerve injury. These findings will aid in the development of therapeutics for orofacial neuropathic pain.