| Part one: The change of attentional inhibition function among migraine sufferers: an event-related potential(ERP)study.Objectives:Migraine has been associated with cognitive decline,and the interaction between pain chronification and alteration in attention is also reported.However,with respect to the attention function of migraineurs,no consistent results has been found,and the relation between attentional inhibition and migraine is also not clear.In this study,to confirm whether migraine induce decline in attentional inhibition,this function was evaluated using event-related potentials(ERPs)while migraine patients and healthy controls performed the attention network test(ANT)or the color-word Stroop task.Methods:In this study,85 migraine patients and 41 age,gender and education-matched healthy controls were enrolled.The ANT test and stroop task were conducted through the E-prime software,and the reation time and correction rate for each participant was recorded automatically.Electroencephalography(EEG)data were recorded from 64 scalp sites,using Ag/AgCl electrodes mounted in an elastic cap.The ERP components were extracted offline via curry 7.0 software and then statistically analysed.Results:1.As to the behavioral data,the migraine group had longer reaction times in both ANT test and stroop task than that of control group,while no difference in correction rates was discovered,besides,the migraineurs had higher scores in conflict control network;2.With respect to ERP components,the amplitudes of N2,early MFN and late MFN were all decreased in migraine group,and the migraine patients had lower P3 amplitude in CZ electrode;3.Obvious difference in conflic control score,N2 amplitude,P3 amplitude,early MFN amplitude and SP amplitude was found between patients with and without allodynia.Conclusions:1.In behavioral evaluation,the migraine suffers showed deficiencies in both overall reaction ability and confict control function,suggested that migraine induces decline in attentional inhibition function;2.According to the analysis of ERP components,the decline of attentional inhibition among migraineurs mainly includes the alteration in conflict monitering,and to some extent,the conflic resolution ability is also harmed;3.Migraine patients with allodynia had severer deficiencies in attentional inhibition than the ones without,supporting the hypothesis that migraine chronification aggravates decline in attentional inhibition function.Part two: The role of toll-like receptor 4 in the development of hyperalgesia induced by dural inflammatory stimuli in rats.Objectives:Although nociceptive sensitisation is an important pathophysiological process in migraine and migraine chronification,its underlying mechanisms remain unclear.Tolllike receptor 4(TLR4),a pattern-recognition molecule,has a critical role in both neuropathic pain and morphine tolerance.The present study examined whether elements of the TLR4 pathway contribute to hyperalgesia induced by dural inflammation in rats.Methods:A rat model of migraine was established by acutely infusing a dural inflammatory soup(IS)or via repeated dural IS infusions(three time-point was setted,including IS-1,IS-3 and IS-7).TAK-242 was pretreated in both acute infusion group and IS-7 group to inhibit activation of TLR4.Both the facial mechanical withdraw threshold and hindpaw thermal withdraw latency of rats were tested to confirm the development of hyperalgesia.The expression of Fos in trigeminal ganglion(TG)and trigeminocervical complex(TCC)was examined by immunofluorescence(IF)assays.The protein levels of TLR4 and its downstream molecules in the trigeminal pathway were examined by both IF and western blot(WB).The expression of activated microglia and astrocytes was also analysed.Levels of interleukin-1 beta(IL-1β),tumour necrosis factor-alpha,and brain-derived neurotrophic factor(BDNF)were measured by enzyme-linked immunosorbent assay.Results:In the acute dural stimulation groups: 1.Acute IS infusion induced time-dependent facial mechanical hyperalgesia,which was blocked by TAK-242 pretreatment,but no difference in thermal hindpaw withdraw latency was found;2.The expression of Fos in trigeminal pathway was upregulated by dural IS infusion;3.The IS stimulus increased production of TLR4 downstream molecules and IL-1β,but no upregulation of the receptor was found;3.Higher levels of microglia activation and BDNF release were observed following administration of the IS,but were alleviated by TAK-242,and the activation of astrocytes in TCC among IS-treated rats was not changed.In the repeated dural stimuli groups: 1.Repeated dural inflammatory stimuli induced progressive decline in facial mechanical withdraw threshold,also alleviated by TAK-242;2.All IS-treated rats(including IS-1,IS-3 and IS-7 group)showed higher expression of Fos in TG and TCC,which was reversed by TAK-242 pretreatment;3.All IS-treated groups had a higher production of TLR4 downstream molecules and IL-1β,but only IS-7 caused upregulation of TLR4;4.Higher levels of microglia activation and BDNF release were observed among all three IS-treated groups,and IS-1 caused more microglia activation than IS-7,but the increase of astrocytes activation was only found in IS-3 and IS-7 group,with TAK-242 pretreatment decreased both the higher activation of microglia and astrocytes;5.The immunofluorescence double-staining proved the expression of TLR4 in both neurons and microglia,but no coexpression of TLR4 and astrocyte marker was found.Conclusions:1.The TLR4 signalling pathway promotes hyperalgesia induced by acute IS delivery by stimulating production of proinflammatory cytokines and activating microglia;2.The progressive hyperalgesia is related to the upregulation of TLR4 and the inflammatory response augmented by the TLR4 signalling pathway;3.Dural inflammatory stimili causes time-sequenced activation of microglia and astrocytes,and TLR4 signalling can not only influence the function state of neurons but also change the neuroimmune function directly targeted at microglia;4.Via blocking the signalling pathway of TLR4,TAK-242 effectively alleviates the hyperalgesia induced by dural inflammation. |
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