Rahman Shafaqat M, Guo Linda Jia, Minarovich Carissa, Moon Laura, Guo Anna, Luebke Anne E
Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States of America.
Department of Neuroscience, Del Monte Institute of Neuroscience, University of Rochester Medical Center, Rochester, NY, United States of America.
PLoS One. 2024 Dec 9;19(12):e0313482. doi: 10.1371/journal.pone.0313482. eCollection 2024.
Both enhanced motion-induced nausea and increased static imbalance are observed symptoms in migraine and especially vestibular migraine (VM). Motion-induced nausea and static imbalance were investigated in a mouse model, nestin/hRAMP1, expressing elevated levels of human RAMP1 which enhances CGRP signaling in the nervous system, and compared to non-affected littermate controls. Behavioral surrogates such as the motion-induced thermoregulation and postural sway center of pressure (CoP) assays were used to assess motion sensitivity. Nausea readouts revealed that the nestin/hRAMP1 mouse exhibit an increased sensitivity to CGRP's effects at lower doses compared to unaffected controls. In addition, the nestin/hRAMP1 mice exhibit a higher dynamic range in postural sway than their wildtype counterparts, along with increased sway observed in nestin/hRAMP1 male mice that was not present in male unaffected controls. Results from migraine blocker experiments were challenging to interpret, but the data suggests that olcegepant is incapable of reversing CGRP-induced or endogenous alterations in the nestin/hRAMP1 mice, while rizatriptan was ineffective in both the nestin/hRAMP1 and control mice. The results indicate that overexpression of hRAMP1 leads to heightened endogenous CGRP signaling. Results also suggest that both olcegepant and rizatriptan are ineffective in reducing nausea and sway in this hypersensitive CGRP mouse model. This study suggests that the hypersensitive nestin/hRAMP1 mouse may serve as a model for difficult to treat cases of migraine that exhibit increased motion sensitivity.
在偏头痛尤其是前庭性偏头痛（VM）中，增强的运动诱发恶心和静态失衡增加是观察到的症状。在一个表达人RAMP1水平升高的小鼠模型nestin/hRAMP1中研究了运动诱发恶心和静态失衡，该模型增强了神经系统中的降钙素基因相关肽（CGRP）信号传导，并与未受影响的同窝对照进行比较。使用行为替代指标，如运动诱发的体温调节和压力中心姿势摆动（CoP）测定，来评估运动敏感性。恶心读数显示，与未受影响的对照相比，nestin/hRAMP1小鼠在较低剂量下对CGRP的作用表现出更高的敏感性。此外，nestin/hRAMP1小鼠在姿势摆动方面的动态范围比野生型对应物更高，并且在nestin/hRAMP1雄性小鼠中观察到的摆动增加在未受影响的雄性对照中不存在。偏头痛阻滞剂实验的结果难以解释，但数据表明，olcegepant无法逆转nestin/hRAMP1小鼠中CGRP诱导的或内源性的改变，而利扎曲普坦在nestin/hRAMP1小鼠和对照小鼠中均无效。结果表明，hRAMP1的过表达导致内源性CGRP信号增强。结果还表明，olcegepant和利扎曲普坦在这个对CGRP过敏的小鼠模型中都无法有效减轻恶心和摆动。这项研究表明，对CGRP过敏的nestin/hRAMP1小鼠可能作为偏头痛难治病例的模型，这些病例表现出运动敏感性增加。
