Nicorandil restores endothelial cell Kir6.2 expression to alleviate neuropathic pain in mice after chronic constriction injury

The clinical management of neuropathic pain (NP) remains a significant challenge, as current pharmacological treatments do not fully meet clinical needs. Nicorandil, a potassium ATP channel agonist widely used in cardiovascular medicine, has recently been shown to have significant potential for analgesia. This study aimed to investigate the effects and mechanisms of nicorandil in a chronic constriction injury (CCI) mouse model. Nicorandil significantly alleviated pain hypersensitivity and reduced neuronal injury in the sciatic nerve (SN) and dorsal root ganglion (DRG) post-CCI. Nicorandil primarily affected endothelial cells and Schwann cells in the sciatic nerve, restoring the expression of the KATP channel subunit Kir6.2. Furthermore, nicorandil attenuated the hypoxia-induced apoptosis program in sciatic nerve endothelial cells, leading to reduced expression of apoptotic proteins, which provided significant endothelial protection, improved blood-nerve barrier leakage, and decreased the release of DRG inflammatory factors and pain neurotransmitter substance P. In vitro, nicorandil attenuated the apoptosis of human umbilical vein endothelial cells (HUVECs) in a hypoxic environment while maintaining cellular functions. In addition, administering the KATP channel inhibitor glibenclamide in vitro further confirmed the crucial role of Kir6.2 in reducing endothelial hypoxic stress, as confirmed by transmission electron microscopy and behavioural experiments. Overall, these findings indicate that nicorandil significantly ameliorates CCI-induced NP in mice by targeting Kir6.2 in sciatic nerve endothelial cells, thus inhibiting pain sensitization.