背景:偏头痛是一种神经系统疾病,其特征是复杂的,广泛,发病机制不清楚的突然发作,特别是在慢性偏头痛(CM)。特定的大脑区域,包括脑岛,杏仁核,丘脑,和扣带回,内侧前额叶,和前扣带皮质,在CM患者和动物模型中通常被疼痛刺激激活。本研究采用荧光显微镜光学切片断层扫描(fMOST)技术和AAV-PHP。eB全脑表达绘制CM小鼠脑区的激活模式,从而增强对CM发病机制的理解并提示潜在的治疗靶点。
方法:通过反复施用硝酸甘油(NTG)诱导小鼠偏头痛样疼痛,建立慢性偏头痛模型(CMM)。然后使用Olcegepant(OLC)作为治疗方法,观察其对机械性疼痛超敏反应和脑区激活的影响。所有小鼠均接受机械戒断阈值,光线厌恶,和高架加迷宫测试。在建模前一个月对小鼠进行病毒注射,最后一次NTG/媒介物对照注射后2小时收集脑样品,用于使用fMOST进行全脑成像。
结果:在NTG诱导的CMM中,机械性痛阈降低,畏光,观察到焦虑样行为,发现OLC改善了这些表现。fMOST全脑成像结果表明,等皮质-大脑皮层板区域,包括躯体运动区(MO),体感区(SS),和主嗅觉灯泡(MOB),似乎是CM中最敏感的激活区域(P<0.05)。其他脑区如下丘(IC)和中间网状核(IRN)也表现出明显的激活(P<0.05)。用OLC治疗观察到的偏头痛样症状的改善可能与其对这些大脑区域的影响有关,特别是SS,MO,管状小叶(AN),IC,三叉神经的脊髓核,尾部(Sp5c),IRN,旁细胞网状核(PARN)(P<0.05)。
结论:fMOST全脑成像显示许多脑区的c-Fos+细胞。OLC通过调节某些大脑区域的大脑活动来改善偏头痛样症状。这项研究证明了NTG诱导的CMM中特定大脑区域的激活,并表明某些区域是OLC的潜在治疗机制。
BACKGROUND: Migraine is a neurological disorder characterized by complex, widespread, and sudden attacks with an unclear pathogenesis, particularly in chronic migraine (CM). Specific brain regions, including the insula, amygdala, thalamus, and cingulate, medial prefrontal, and anterior cingulate cortex, are commonly activated by pain stimuli in patients with CM and animal models. This study employs fluorescence microscopy optical sectioning tomography (fMOST) technology and AAV-PHP.eB whole-brain expression to map activation patterns of brain regions in CM mice, thus enhancing the understanding of CM pathogenesis and suggesting potential treatment targets.
METHODS: By repeatedly administering nitroglycerin (NTG) to induce migraine-like pain in mice, a chronic migraine model (CMM) was established. Olcegepant (OLC) was then used as treatment and its effects on mechanical pain hypersensitivity and brain region activation were observed. All mice underwent mechanical withdrawal threshold, light-aversive, and elevated plus maze tests. Viral injections were administered to the mice one month prior to modelling, and brain samples were collected 2 h after the final NTG/vehicle control injection for whole-brain imaging using fMOST.
RESULTS: In the NTG-induced CMM, mechanical pain threshold decreased, photophobia, and anxiety-like behavior were observed, and OLC was found to improve these manifestations. fMOST whole-brain imaging results suggest that the isocortex-cerebral cortex plate region, including somatomotor areas (MO), somatosensory areas (SS), and main olfactory bulb (MOB), appears to be the most sensitive area of activation in CM (P < 0.05). Other brain regions such as the inferior colliculus (IC) and intermediate reticular nucleus (IRN) were also exhibited significant activation (P < 0.05). The improvement in migraine-like symptoms observed with OLC treatment may be related to its effects on these brain regions, particularly SS, MO, ansiform lobule (AN), IC, spinal nucleus of the trigeminal, caudal part (Sp5c), IRN, and parvicellular reticular nucleus (PARN) (P < 0.05).
CONCLUSIONS: fMOST whole-brain imaging reveals c-Fos + cells in numerous brain regions. OLC improves migraine-like symptoms by modulating brain activity in some brain regions. This study demonstrates the activation of the specific brain areas in NTG-induced CMM and suggests some regions as a potential treatment mechanism according to OLC.