Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonism Reduces Motion Sickness Indicators in Mouse Migraine Models

Abstract

Migraine and vestibular migraine (VM) are associated with enhanced motion sensitivity, and VM is the most common cause of spontaneous vertigo but remains poorly understood. It is now accepted that migraine involves the neuropeptide Calcitonin Gene-Related Peptide (CGRP); yet it is not clear if CGRP signaling or its antagonism is involved in motion sensitivity of VM symptoms. Recent murine models of migraine used injections of CGRP or other migraine triggers (sodium nitroprusside SNP) to induce migraine sensitivities, yet it is not known if these triggers can induce VM sensitivities. Moreover, it is not known if migraine blockers used in preclinical migraine models, can also block the motion-sensitivity of VM. To better understand CGRP signallingin VM motion sensitivity, we investigated two measures of motion sickness assessment (MSI scoring and motion-induced thermoregulation) after systemic injections of either CGRP or SNP in the wildtype C57B6/J mice, and found that MSI measures were confounded by CGRPs effect on based on gastric distress, yet assessing motion sensitivity using thermoregulation was robust for both migraine triggers, and CGRP receptor antagonism by olcegepant, but not triptan treatments, rescued CGRPs effect on increased motion sensitivity.

Aged mice are less susceptible to motion sickness and show decreased efferent vestibular activity compared to young adults

“…Our findings in a further two mouse strains are consistent with that study and another recent murine motion sickness study (Rahman & Luebke, 2022). In young adult C57BL/6 and transgenic ChAT-gCaMP6 f mice, we found similar T tail responses, although ChAT-gCaMP6 f mice showed an elevated peak T tail compared to C57BL/6 mice within 6-7 min of PM onset (Figure 4a).…”

“…While sexual dimorphism is of interest, it was not an aim of this study to compare male and female mice since we only had access to males in the aged group. By chance, we had a predominantly female representation in young adult cohorts, but we suggest it should not influence our agedependent results significantly since Rahman and Luebke (2022) show there were no differences in PM response between young adult males and females.…”

“…These include pica, the consumption of nonnutritious substances (Mitchell et al., 1977 ; Morita et al., 1988 ), increased defecation (Ossenkopp & Frisken, 1982 ), suppression of drinking (Haroutunian et al., 1976 ), and thermal responses such as transient increasing tail temperature ( T tail ) and decreasing core body temperature (Del Vecchio et al., 2014 ; Guimaraes et al., 2015 ; Ngampramuan et al., 2014 ). It has been previously reported by our group (Tu et al., 2017 ) and others (Rahman & Luebke, 2022 ) that these thermal responses are a robust and accurate indicator of motion sickness in laboratory mice and can be recorded simply using infrared imaging. We used this method to monitor the response to provocative motion (PM) in different mouse strains and an aged cohort.…”

Migraine inhibitor olcegepant reduces weight loss and IL-6 release in SARS-CoV-2 infected older mice with neurological signs

“…In the nausea/dizziness assay after provocative motion there is a decrease in head temperature and an increase in tail temperature. We have shown that in wildtype C57BL/6J mice injection of CGRP prolongs the head temperature response and blunts the transient tail temperature increase, whereas a CGRP-receptor antagonist can reverse these CGRP-induced changes (21,27,28). Therefore, we investigated if a MA10-SARS-CoV-2 viral infection would show similar acute dizziness/nausea responses as CGRP injection, and if antagonizing CGRP signaling could reduce these dizziness/nausea responses and/or other signs of SARS-CoV-2 infection.…”

“…We used MA10-SARS-CoV-2 to assess both neurological symptoms of fever and dizziness/nausea in mouse models after infection. As a readout of the nausea-like state present after SARS-CoV-2 infection, we examined hypothermic responses to provocative motion, as we have previously used to assess migraine nausea pain (21) and others have used to assess motion-sensitivity in transgenic mouse models (22). Studies have demonstrated that provocative motion causes robust and prominent hypothermic responses in rats, humans, house musk shrews, and mice.…”