Quercetin Alleviates Neuropathic Pain in the Rat CCI Model by Mediating AMPK/MAPK Pathway

Guangyao Ye,1,* Chunyan Lin,1,* Yu Zhang,1 Zihan Ma,2 Yuebo Chen,1 Lingsi Kong,1 Liyong Yuan,1 Tao Ma3 1Department of Anesthesiology, Ningbo No.6 Hospital, Ningbo, 315040, People’s Republic of China; 2School of Medicine, Ningbo University, Ningbo, 315211, People’s Republic of China; 3Department of Anesthesiology and Pharmacology, Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liyong YuanDepartment of Anesthesiology, Ningbo No.6 Hospital, Ningbo, 315040, People’s Republic of ChinaEmail yuanl1973@yeah.netTao MaDepartment of Anesthesiology and Pharmacology, Xuzhou Medical University, Xuzhou, 221000, People’s Republic of ChinaEmail Matao201006@126.comContext: Quercetin (que) is one abundant flavonol with a variety of biological activities. Previous studies have shown quercetin can reduce neuropathic pain in rats with chronic constriction injury (CCI).Objective: To evaluate the effects of quercetin on neuropathic pain in CCI model and explore its underlying mechanism in vivo.Materials and Methods: CCI model was established by ligating the sciatic nerve of right leg on the SD rats. They were divided into ten groups: sham group, CCI model, sham+ que, CCI+ que group (30, 60, 120 mg/kg), CCI+ AICAR, CCI+ que+ compound C, CCI+etoricoxib, and the control group. They were administered for 28 days, and were performed the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) during the experiment. At the end of the experiment, sciatic nerves and spinal cord segments of rats were collected, ELISA detected the expression of inflammatory factors, detected the microglia and astrocytes with fluorescence, and Western blot detected AMPK/MAPK pathway.Results: Que could increase the MWT of CCI rats, improve the TWL of plantar, and reduce the inflammatory cells at the ligation site of the sciatic nerve. Also, que could reduce the levels of TNF-α, IL-6, and IL-1β. Western blotting results showed that p-38 MAPK, p-ERK, and p-JNK were activated in the spinal dorsal horn of CCI model group. After treatment with que and AMPK agonists, the phosphorylation levels of related proteins were inhibited. In addition, the analgesic effect of que was abolished when the AMPK inhibitor was added.Discussion and Conclusion: Quercetin alleviated the inflammatory response of sciatic nerve and spinal dorsal horn in rats induced by CCI. Quercetin alleviates neuralgia in CCI rats by activating AMPK pathway and inhibiting MAPK pathway and its downstream targets, p-38, p-ERK, and p-JNK.Keywords: quercetin, neuropathic pain, AMPK, MAPK, CCI