The Effcets Of Microglia NLRP3 Inflammasome In Central Sensitization In Chronic Migraine Mice

Background: Central sensitization is an important mechanism of chronic migraine(CM).Recent studies in different pain models have shown that central sensitization is related to the inflammatory response of microglia.The NOD-like receptor protein 3(NLRP3)inflammasome may regulate the inflammatory process of microglia in several neurological diseases,but its role in CM is unclear.Objective: The aim of this study was to explore the role and mechanism of NLRP3 inflammasome in the pathological process of central sensitization in CM mice.Methods: We established the CM mouse models by repeated intraperitoneal(i.p)injection with nitroglycerin(NTG).We detected the protein expression levels of NLRP3 and its downstream interleukin(IL)-1?in the trigeminal nucleus caudalis(TNC)at different time points.Then,we observed that whether the NLRP3 and IL-1? expressed in microglia in the TNC.To further validate the NLRP3/ IL-1? pathway contributed to central sensitization of CM,we used the NLRP3 inhibitor MCC950 and the IL-1?antagonist IL-1ra,to observe the changes of NTG-induced mechanical hyperalgesia of the periorbital area and hind paw.In addition,we observed the changes of the expression of migraine-associated marker CGRP and neuronal activation marker c-Fos,p-ERK in the TNC.Result: Repeated NTG administration induced increased expression of NLRP3 and IL-1?.Blockade of NLRP3 or IL-1? reduced NTG-induced acute and chronic hyperalgesia,and significant inhibited the increased expression levels of p-ERK,c-Fos and CGRP in the TNC induced by NTG.Immunofluorescence staining revealed that NLRP3 and IL-1? were expressed in microglia in the TNC,and the IL-1? receptor,IL-1R,was mainly expressed in neurons in the TNC.Conclusions: This study demonstrates for the first time that NLRP3 inflammasome was up-regulated in TNC of CM mice model which induced by repeated NTG injections,and inhibiting NLRP3 inflammasome could improve the hyperalgesia of CM mice.In addition,this study showed that the microglia NLRP3 participates in the microglial-neuronal signal might be through by the IL-1?/IL-1R pathway,and this process contributes to the central sensitization.NLRP3 inflammasome may be a potential and new therapeutic target for CM.