Journal Article

Human RAMP1 overexpressing mice are resistant to migraine therapies for motion sensitivity

Rahman, Shafaqat M., Luebke, Anne E., Guo, Anna, Moon, Laura, Minarovich, Carissa, Guo, Linda Jia

2024

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Behavior / Biology and Life Sciences / Calcitonin gene-related peptide / Calcitonin Gene-Related Peptide - genetics / Calcitonin Gene-Related Peptide - metabolism / Center of pressure / Disease Models, Animal / Female / Headache / Human motion / Humans / Hypothermia / Male / Males / Medicine and Health Sciences / Mice / Mice, Transgenic / Migraine / Migraine Disorders - drug therapy / Migraine Disorders - genetics / Migraine Disorders - metabolism / Migraine Disorders - physiopathology / Nausea / Nausea - drug therapy / Nausea - genetics / Nervous system / Nestin / Peptides / Posture / Proteins / Receptor activity modifying proteins / Receptor Activity-Modifying Protein 1 - genetics / Receptor Activity-Modifying Protein 1 - metabolism / Research and Analysis Methods / Sensitivity analysis / Social Sciences / Temperature / Thermoregulation / Vertigo / Vestibular system