Calcitonin Gene-related Peptide Facilitates Sensitization Of The Vestibular Nucleus In A Rat Model Of Chronic Migraine

Background: Vestibular migraine has recently been recognized as a novel subtype of migraine.However,the mechanism that relate vestibular symptoms to migraine had not been well elucidated.Thus,the present study investigated vestibular dysfunction in a rat model of chronic migraine(CM),and to dissect potential mechanisms between migraine and vertigo.Methods: Rats subjected to recurrent intermittent administration of nitroglycerin(NTG)were used as the CM model.Thermal hyperalgesia,head grooming,balance beam walk,negative geotaxis and vestibular dysfunction scores were used to examine the migraine-and vestibular-related behaviors.Immunofluorescent analyses and quantitative real-time polymerase chain reaction were employed to detect expressions of c-fos and calcitonin gene-related peptide(CGRP)in the trigeminal nucleus caudalis(TNC)and vestibular nucleus(VN).Morphological changes of vestibular afferent terminals was determined under transmission electron microscopy.To confirm whether trigeminovestibular neurons were activated by CM,FluoroGold(FG)and CTB-555 were selected asretrograde tracers and injected into the VN and TNC,respectively.To further investigate the effect of CGRP on the neuronal activation and vestibular-mediated behaviors,lentiviral vectors comprising CGRP short hairpin RNA(LV-CGRP)was injected into the trigeminal ganglion.Results: Chronic intermittent administration of NTG led to persistent thermal hyperalgesia,spontaneous facial pain,and prominent vestibular dysfunction,accompanied by the upregulation of c-fos labeling neurons and CGRP expression in the TNC and VN.Furthermore,FG-positive neurons was accumulated in the superficial layer of the TNC,and the number of c-fos+/FG+ neurons were significantly increased in rats with CM compared to the vehicle group.Meanwhile,CTB-555+ neurons dispersed throughout the VN.The structure of vestibular afferent terminals was less pronounced after CM compared with the peripheral vestibular dysfunction model.In vivo knockdown of CGRP in the trigeminal ganglion significantly reduced the number of c-fos labeling neurons and CGRP expression in the VN,further attenuating vestibular dysfunction after CM.Conclusions: These data demonstrates the possibility of sensitization of vestibular nucleus neurons to impair vestibular function after CM,and anti-CGRP treatment to restore vestibular dysfunction in patients with CM.