Role of Calcitonin Gene-Related Peptide (CGRP) in Auditory, Static, and Dynamic Imbalance Behaviors: Implications for Vestibular Migraine

Abstract

Migraine is a severe and chronic neurological disorder that affects [~]18% of people worldwide, the majority being female (3:1). It is characterized by recurrent, debilitating headaches and heightened sensory sensitivities. People with migraine may develop vestibular migraine (VM), characterized by a heightened motion sensitivity and preponderance for spontaneous vertigo attacks and balance problems such as postural instability. Calcitonin gene-related peptide (CGRP) is implicated in migraine and is believed to act on brain meninges or in subcortical central nervous system (CNS) structures, and CGRP-based antagonists have shown efficacy for migraine treatment. CGRP also signals at efferent synapses of the cochlea and vestibular end organs, but it is unclear if exogenous CGRP can modulate inner ear function at the end organ level and cause heightened behavioral responses consistent with VM. We tested if intraperitoneally (IP) delivered CGRP to wildtype mice can modulate end organ potentials to sound [via auditory brainstem responses (ABRs)] and jerk stimuli [via vestibular sensory evoked potentials (VsEPs)]. We also assessed behavioral measures of phonophobia [acoustic startle reflex (ASR)] and static imbalance [postural sway-center of pressure (CoP)] after IP CGRP, and observed female mice exhibited heightened sensitivities to IP CGRP in all assays. Male mice showed similar auditory sensitivity and end organ effects to CGRP, but systemic CGRP did not modify male postural sway as it did in females. In conclusion, we show that intraperitoneally delivered CGRP affects ABRs and VsEPs, and elicits behaviors suggestive of auditory hypersensitivity and postural instability in mice related to the phonophobia and postural instability seen in VM patients. Significance StatementCalcitonin Gene-Related Peptide (CGRP) has been implicated in migraine, and CGRP-based therapeutics have shown efficacy in the treatment of migraine headaches. CGRP is also present in efferent synapses of the inner ear, so we questioned if increases in systemic CGRP can act directly on inner ear end organs and modify corresponding behavioral responses. In this study, we determined systemic CGRP changes cochlear and vestibular end organ potentials and produces migraine behaviors similar to phonophobia and postural control deficits. Peripheral changes in auditory and vestibular compound action potentials following systemic CGRP administration suggest CGRP can act directly on the inner ear, which provides one site of action for CGRPs involvement in hypersensitivity to sound and movement in migraine.