偏头痛与丛集性头痛的疼痛发生机制研究
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摘要
目的
1.观察大鼠皮层扩布性抑制(CSD)前、中、后三叉神经脊束核尾侧亚核(TNC)神经元放电频率的变化,以及盐酸氟桂利嗪对其的影响,以了解CSD与三叉神经血管反射中枢之间的联系。
2.建立大鼠CSD模型,观察血浆和三叉神经节CGRP、SP的变化以及盐酸氟桂利嗪对此的影响,进一步了解CSD与三叉神经血管反射周围机制之间的联系。
3.利用静息态fMRI技术分析丛集性头痛患者丛集期内头痛自发发作时脑活动的变化以及全脑与感兴趣区之间的功能联系,以了解丛集性头痛的疼痛发生机制。
方法
1.大鼠分为对照组、同侧TNC组、对侧TNC组、氟桂利嗪组,对照组用生理盐水刺激,其余三组用氯化钾刺激建立CSD模型,刺激前5分钟静脉给予盐酸氟桂利嗪。利用玻璃微电极同时记录CSD和同侧或对侧TNC神经元单细胞放电胞外记录,采用PowerLab计算机数据采集系统及Chart5.0 for Windows分析软件进行数据采集并分析CSD前、中、后TNC神经元的放电频率。
2.大鼠随机分为对照组、CSD组、氟桂利嗪组,用氯化钾刺激建立CSD模型,对照组用生理盐水刺激,刺激前5分钟静脉给予盐酸氟桂利嗪。利用放射免疫技术测定大鼠血浆以及双侧三叉神经节中的CGRP、SP水平;利用免疫组化技术检测大鼠双侧三叉神经节中CGRP、SP免疫反应阳性情况。
3.20例男性丛集性头痛患者,分为右侧头痛组(12例)、左侧头痛组(8例),头痛自发发作期间以及头痛缓解期分别接受静息态fMRI扫描,利用局部一致性(ReHo)分析和功能连接分析方法处理所得数据。
结果
1.对照组未发现CSD;同侧TNC放电频率,CSD中＞CSD后＞CSD前(P＜0.05);对侧TNC放电频率,CSD前、中、后无统计学差异(P＞0.05);氟桂利嗪组同侧TNC放电频率,CSD前＞CSD中(P＜0.05),CSD前与CSD后及CSD中与CSD后之间无统计学差异(P＞0.05)。
2.1)关于放免测定,各组血浆CGRP、SP水平有统计学差异(P＜0.05),CSD组高于对照组(P＜0.05),CSD组与氟桂利嗪组、对照组与氟桂利嗪组之间均无统计学差异(P＞0.05);各组之间同侧三叉神经节中CGRP、SP水平未见变化(P＞0.05)。
2)关于免疫组化研究,右侧三叉神经节CGRP、SP免疫阳性细胞数三组之间有统计学差异(P＜0.05),多重两两比较结果CSD组大于对照组(P＜0.05),CSD组与氟桂利嗪组之间、对照组与氟桂利嗪组之间无统计学差异(P＞0.05);左侧三叉神经节CGRP、SP免疫阳性细胞数三组之间无统计学差异(P＞0.05);CSD组中右侧三叉神经节CGRP、SP免疫反应阳性细胞数大于左侧(P＜0.05)。
3.1)局部一致性分析发现两组患者头痛疼痛状态较非疼痛状态脑活动发生变化的脑区有同侧脑桥以及其他疼痛相关脑区如基底节区、丘脑、扣带回、前额叶皮层等(P＜0.05,蒙特卡罗模拟校正)。
2)功能连接分析发现疼痛状态与非疼痛状态下主要疼痛相关脑区均与同侧脑桥有功能联系(P＜0.05,false discovery rate,FDR校正);疼痛状态与非疼痛状态比较,同侧前额叶皮层、对侧胼胝下回等疼痛相关脑区与同侧脑桥之间功能联系增强(P＜0.05,蒙特卡罗模拟校正)。
结论
1.CSD使同侧TNC神经元放电频率增加,盐酸氟桂利嗪干预后,同侧TNC神经元放电频率于CSD发生期间下降,说明CSD可能通过一定的机制激活三叉神经血管反射中枢,盐酸氟桂利嗪可能通过抑制这一过程来有效预防偏头痛。
2.CSD使血浆CGRP、SP水平增加,使同侧三叉神经节CGRP、SP免疫阳性细胞数增加,说明CSD可能通过一定的机制激活了三叉神经血管反射的周围机制。
3.同侧脑桥活动增强可能通过三叉神经副交感反射参与了丛集性头痛的疼痛发生机制,其他疼痛相关脑区如扣带回和前额叶皮层等可能也参与了其疼痛发生机制。
Objective
1.To observe the effect of cortical spreading depression(CSD) on firing rate of trigeminal nucleus caudalis(TNC) neurons in rats so as to determine the correlation between CSD and central trigeminovascular neurons.
2.To investigate the effect of CSD on CGRP and SP levels in serum and trigeminal ganglia in rats so as to determine the correlation between CSD and peripheral trigeminovascular neurons.
3.To examine the changes of brain activity and functional correlations during spontaneous cluster headache attack as compared with during remission in the cluster period of patients with cluster headache by using resting-state functional magnetic resonance imaging(fMRI).
Methods
1.The rats were divided into four goups,including control group,ipsilateral TNC group,contralateral TNC group,and flunarizine group.The CSD waves were evoked by application of potassium chloride on brain surface with filter paper.For control group,saline,instead of potassium chloride,was used for stimulation on brain surface with filter paper.For flunarizine group, funarizine hydrochloride was intravenously administered to rats five minutes prior to application of potassium chloride.CSD waves and extracellular single-unit recordings in the site of TNC were simultaneously recorded by glass microelectrodes.The data of CSD and firing rates of TNC neurons were collected by PowerLab system and analysed by Chart5.0 for Windows software.
2.The rats were randomly divided into three goups,including control group, CSD group,and flunarizine group.The levels of CGRP and SP in plasma and trigeminal ganglia were measured by radioimmunity assay.The neurons with positive CGRP and SP immunoreactivity in trigeminal ganglia were identified by immunohistochemistry technique.
3.Twenty male patients with episodic cluster headache were divided into two groups including right-sided headache group and left-sided headache group. Two resting-fMRI scans were successfully acquired respectively during the acute spontaneous attack and again during headache remission.The changes of brain activity and functional correlations between the whole brain and region of interest(ROI) were respectively analysed by the regional homogeneity(ReHo) method and functional connectivity method.
Results
1.There was no CSD wave in control group.The firing rates in the site of ipsilateral TNC neuron during CSD were higher as compared with during post-CSD,and the later were higher as compared with during pre-CSD(P＜0.05).There were no significant differences for the firing rates in the site of contralateral TNC neurons among during pre-CSD,CSD,and post-CSD (P＞0.05).For flunarizine group,the firing rates in the site of ipsilateral TNC neurons during pre-CSD were higher as compared with during CSD(P＜0.05).
2.1) There were statistical differences on palasma levels of CGRP and SP among the three groups(P＜0.05).The levels of CGRP and SP in CSD group were higher than control group(P＜0.05).No significant differences on the levels of CGRP and SP in ipsilateral trigeminal ganglia were found among the three groups(P＞0.05).
2) The number of neurons with positive CGRP and SP immunoreactivity was statistically different in right-sided trigeminal ganglia among the three groups (P＜0.05).The number in fight-sided trigeminal ganglia in CSD group was higher as compared with control group(P＜0.05).The number in right-sided trigeminal ganglia was statistically higher than that in left-sided trigeminal ganglion in CSD group(P＜0.05).
3.1) Altered ReHo in ipsilateral pons and other brain regions response to pain such as basal nuclei,thalamus,cingulated gyms and prefrontal cortex was detected during the acute spontaneous attack as compared with during headache remission(P＜0.05,corrected by Monte Carlo simulation). 2) Positive functional connectivity was detected between ipsilateral pons and other brain regions related to pain within pain state and within non-pain state (P＜0.05,corrected by false discovery rate,FDR).Increased functional correlation between ipsilateral pons and other pain-related brain regions such as ipsilateral prefrontal cortex and contralateral subcallosal gyrus was detected during the acute spontaneous attack as compared with during headache remission(P＜0.05,corrected by Monte Carlo simulation).
Conclusion
1.The firing rates in the site of ipsilateral TNC neurons are increased by CSD, and decreased after intravenous administration of flunarizine hydrochloride.It is inferred that CSD may activate central trigeminovascular neuron through certain mechanism,and flunarizine hydrochloride may prevent migraine by inhibiting the process.
2.CSD increases the serum level of CGRP and SP and the number of CGRP and SP positive immunoreactivity neurons in ipsilateral trigemnal ganglia.It is implicated that CSD may activate peripheral trigeminovascular reflex.
3.Our findings suggest that increased brain activity in ipsilateral pons involved in trigeminal vascular reflex may be related to the pathogenesis of pain in cluster headache.Other brain regions known to be response to pain,such as cingulated gyrus and prefrontal cortex might be also involved in CH attack processing.
1.观察大鼠皮层扩布性抑制(CSD)前、中、后三叉神经脊束核尾侧亚核(TNC)神经元放电频率的变化,以及盐酸氟桂利嗪对其的影响,以了解CSD与三叉神经血管反射中枢之间的联系。
2.建立大鼠CSD模型,观察血浆和三叉神经节CGRP、SP的变化以及盐酸氟桂利嗪对此的影响,进一步了解CSD与三叉神经血管反射周围机制之间的联系。
3.利用静息态fMRI技术分析丛集性头痛患者丛集期内头痛自发发作时脑活动的变化以及全脑与感兴趣区之间的功能联系,以了解丛集性头痛的疼痛发生机制。
方法
1.大鼠分为对照组、同侧TNC组、对侧TNC组、氟桂利嗪组,对照组用生理盐水刺激,其余三组用氯化钾刺激建立CSD模型,刺激前5分钟静脉给予盐酸氟桂利嗪。利用玻璃微电极同时记录CSD和同侧或对侧TNC神经元单细胞放电胞外记录,采用PowerLab计算机数据采集系统及Chart5.0 for Windows分析软件进行数据采集并分析CSD前、中、后TNC神经元的放电频率。
2.大鼠随机分为对照组、CSD组、氟桂利嗪组,用氯化钾刺激建立CSD模型,对照组用生理盐水刺激,刺激前5分钟静脉给予盐酸氟桂利嗪。利用放射免疫技术测定大鼠血浆以及双侧三叉神经节中的CGRP、SP水平;利用免疫组化技术检测大鼠双侧三叉神经节中CGRP、SP免疫反应阳性情况。
3.20例男性丛集性头痛患者,分为右侧头痛组(12例)、左侧头痛组(8例),头痛自发发作期间以及头痛缓解期分别接受静息态fMRI扫描,利用局部一致性(ReHo)分析和功能连接分析方法处理所得数据。
结果
1.对照组未发现CSD;同侧TNC放电频率,CSD中＞CSD后＞CSD前(P＜0.05);对侧TNC放电频率,CSD前、中、后无统计学差异(P＞0.05);氟桂利嗪组同侧TNC放电频率,CSD前＞CSD中(P＜0.05),CSD前与CSD后及CSD中与CSD后之间无统计学差异(P＞0.05)。
2.1)关于放免测定,各组血浆CGRP、SP水平有统计学差异(P＜0.05),CSD组高于对照组(P＜0.05),CSD组与氟桂利嗪组、对照组与氟桂利嗪组之间均无统计学差异(P＞0.05);各组之间同侧三叉神经节中CGRP、SP水平未见变化(P＞0.05)。
2)关于免疫组化研究,右侧三叉神经节CGRP、SP免疫阳性细胞数三组之间有统计学差异(P＜0.05),多重两两比较结果CSD组大于对照组(P＜0.05),CSD组与氟桂利嗪组之间、对照组与氟桂利嗪组之间无统计学差异(P＞0.05);左侧三叉神经节CGRP、SP免疫阳性细胞数三组之间无统计学差异(P＞0.05);CSD组中右侧三叉神经节CGRP、SP免疫反应阳性细胞数大于左侧(P＜0.05)。
3.1)局部一致性分析发现两组患者头痛疼痛状态较非疼痛状态脑活动发生变化的脑区有同侧脑桥以及其他疼痛相关脑区如基底节区、丘脑、扣带回、前额叶皮层等(P＜0.05,蒙特卡罗模拟校正)。
2)功能连接分析发现疼痛状态与非疼痛状态下主要疼痛相关脑区均与同侧脑桥有功能联系(P＜0.05,false discovery rate,FDR校正);疼痛状态与非疼痛状态比较,同侧前额叶皮层、对侧胼胝下回等疼痛相关脑区与同侧脑桥之间功能联系增强(P＜0.05,蒙特卡罗模拟校正)。
结论
1.CSD使同侧TNC神经元放电频率增加,盐酸氟桂利嗪干预后,同侧TNC神经元放电频率于CSD发生期间下降,说明CSD可能通过一定的机制激活三叉神经血管反射中枢,盐酸氟桂利嗪可能通过抑制这一过程来有效预防偏头痛。
2.CSD使血浆CGRP、SP水平增加,使同侧三叉神经节CGRP、SP免疫阳性细胞数增加,说明CSD可能通过一定的机制激活了三叉神经血管反射的周围机制。
3.同侧脑桥活动增强可能通过三叉神经副交感反射参与了丛集性头痛的疼痛发生机制,其他疼痛相关脑区如扣带回和前额叶皮层等可能也参与了其疼痛发生机制。
Objective
1.To observe the effect of cortical spreading depression(CSD) on firing rate of trigeminal nucleus caudalis(TNC) neurons in rats so as to determine the correlation between CSD and central trigeminovascular neurons.
2.To investigate the effect of CSD on CGRP and SP levels in serum and trigeminal ganglia in rats so as to determine the correlation between CSD and peripheral trigeminovascular neurons.
3.To examine the changes of brain activity and functional correlations during spontaneous cluster headache attack as compared with during remission in the cluster period of patients with cluster headache by using resting-state functional magnetic resonance imaging(fMRI).
Methods
1.The rats were divided into four goups,including control group,ipsilateral TNC group,contralateral TNC group,and flunarizine group.The CSD waves were evoked by application of potassium chloride on brain surface with filter paper.For control group,saline,instead of potassium chloride,was used for stimulation on brain surface with filter paper.For flunarizine group, funarizine hydrochloride was intravenously administered to rats five minutes prior to application of potassium chloride.CSD waves and extracellular single-unit recordings in the site of TNC were simultaneously recorded by glass microelectrodes.The data of CSD and firing rates of TNC neurons were collected by PowerLab system and analysed by Chart5.0 for Windows software.
2.The rats were randomly divided into three goups,including control group, CSD group,and flunarizine group.The levels of CGRP and SP in plasma and trigeminal ganglia were measured by radioimmunity assay.The neurons with positive CGRP and SP immunoreactivity in trigeminal ganglia were identified by immunohistochemistry technique.
3.Twenty male patients with episodic cluster headache were divided into two groups including right-sided headache group and left-sided headache group. Two resting-fMRI scans were successfully acquired respectively during the acute spontaneous attack and again during headache remission.The changes of brain activity and functional correlations between the whole brain and region of interest(ROI) were respectively analysed by the regional homogeneity(ReHo) method and functional connectivity method.
Results
1.There was no CSD wave in control group.The firing rates in the site of ipsilateral TNC neuron during CSD were higher as compared with during post-CSD,and the later were higher as compared with during pre-CSD(P＜0.05).There were no significant differences for the firing rates in the site of contralateral TNC neurons among during pre-CSD,CSD,and post-CSD (P＞0.05).For flunarizine group,the firing rates in the site of ipsilateral TNC neurons during pre-CSD were higher as compared with during CSD(P＜0.05).
2.1) There were statistical differences on palasma levels of CGRP and SP among the three groups(P＜0.05).The levels of CGRP and SP in CSD group were higher than control group(P＜0.05).No significant differences on the levels of CGRP and SP in ipsilateral trigeminal ganglia were found among the three groups(P＞0.05).
2) The number of neurons with positive CGRP and SP immunoreactivity was statistically different in right-sided trigeminal ganglia among the three groups (P＜0.05).The number in fight-sided trigeminal ganglia in CSD group was higher as compared with control group(P＜0.05).The number in right-sided trigeminal ganglia was statistically higher than that in left-sided trigeminal ganglion in CSD group(P＜0.05).
3.1) Altered ReHo in ipsilateral pons and other brain regions response to pain such as basal nuclei,thalamus,cingulated gyms and prefrontal cortex was detected during the acute spontaneous attack as compared with during headache remission(P＜0.05,corrected by Monte Carlo simulation). 2) Positive functional connectivity was detected between ipsilateral pons and other brain regions related to pain within pain state and within non-pain state (P＜0.05,corrected by false discovery rate,FDR).Increased functional correlation between ipsilateral pons and other pain-related brain regions such as ipsilateral prefrontal cortex and contralateral subcallosal gyrus was detected during the acute spontaneous attack as compared with during headache remission(P＜0.05,corrected by Monte Carlo simulation).
Conclusion
1.The firing rates in the site of ipsilateral TNC neurons are increased by CSD, and decreased after intravenous administration of flunarizine hydrochloride.It is inferred that CSD may activate central trigeminovascular neuron through certain mechanism,and flunarizine hydrochloride may prevent migraine by inhibiting the process.
2.CSD increases the serum level of CGRP and SP and the number of CGRP and SP positive immunoreactivity neurons in ipsilateral trigemnal ganglia.It is implicated that CSD may activate peripheral trigeminovascular reflex.
3.Our findings suggest that increased brain activity in ipsilateral pons involved in trigeminal vascular reflex may be related to the pathogenesis of pain in cluster headache.Other brain regions known to be response to pain,such as cingulated gyrus and prefrontal cortex might be also involved in CH attack processing.
引文
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