Kir4.1 Regulates The Orofacial Pain After Trigeminal Nerve Injury

Aim or purpose: Kir4.1 emerged as a novel therapeutic target for nervous system diseases, such as depression. However, the role and mechanism of Kir4.1 in peripheral and central sensitization after trigeminal neuropathic pain is still unclear. Materials and methods: A chronic constriction injury of the infraorbital nerve (CCI-ION) model was established, and orofacial mechanical hypersensitivity was assessed using the Von Frey test. Immunofluorescence was performed to detect ATF3, c-Fos, GFAP, and Kir4.1 in the trigeminal ganglion (TG) and spinal trigeminal subnucleus caudalis (SpVc). AAV2/8-mediated knockdown or overexpression of Kir4.1 was conducted in TG and SpVc of WT and Kir4.1f/f mice. RT-qPCR and western blot were used to analyze the expression of Kir4.1 and its downstream signaling molecules. Experiments were approved by the Zhejiang University School of Medicine. Results: CCI-ION induced orofacial hypersensitivity and upregulated ATF3 in TG and c-Fos in SpVc, confirming trigeminal nerve injury. Kir4.1 was predominantly expressed in satellite glial cells (SGCs) of TG and astrocytes of SpVc. CCI-ION downregulated Kir4.1, GLAST, and GLT-1 while upregulating BDNF and GDNF in TG and SpVc. Kir4.1 knockdown in SGCs or astrocytes exacerbated pain hypersensitivity, decreased GLAST and GLT-1, and increased BDNF and GDNF expression. Conversely, Kir4.1 overexpression alleviated pain hypersensitivity and reversed these molecular changes. Conclusions: Kir4.1 in SGCs and astrocytes regulates neurotrophic factors (BDNF, GDNF) and glutamate transporters (GLAST, GLT-1), suggesting Kir4.1 as a potential therapeutic target for trigeminal neuropathic pain.