Systemic Calcitonin Gene-Related Peptide (CGRP) modifies auditory and vestibular endorgan electrical potentials, and increases auditory and vestibular hypersensitivities: Implications for vestibular migraine

Abstract

AbstractMigraine 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 also experience a heightened motion sensitivity that leads to episodes of vertigo and imbalance, termed vestibular migraine (VM). Calcitonin Gene-Related Peptide (CGRP) is implicated in migraine and is believed to act on brain meninges, midbrain, or brainstem, and CGRP-based therapeutics have shown efficacy for migraine treatment. CGRP also signals at efferent synapses of the cochlea and vestibular endorgans, but it is unclear if exogenous CGRP can modulate inner ear function and cause heightened behavioral responses consistent with VM. In C57BL/6 mice, we tested if intraperitoneally (IP) delivered CGRP can modulate endorgan potentials to sound [via auditory brainstem responses (ABRs)] and jerk stimulus [via vestibular sensory evoked potentials (VsEPs)]. We also assessed behavioral measures of phonophobia [acoustic startle reflex (ASR)] and imbalance [postural sway-center of pressure (CoP)] after IP CGRP, and observed female mice exhibit heightened sensitivities to IP CGRP in all assays. Male mice showed similar auditory sensitivity and endorgan effects, but no postural sway changes. In conclusion, we show that systemically delivered CGRP modulates the nerve activity of the auditory and vestibular endorgans and elicits behavioral effects that are consistent with symptoms in a disorder like VM.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, but we questioned if increases in systemic CGRP can act directly on inner ear endorgans and modify corresponding behavioral responses. In this study, we determined systemic CGRP changes cochlear and vestibular endorgan potentials and produces behaviors suggestive of phonophobia and postural sway. Peripheral changes in auditory and vestibular compound action potentials following systemic CGRP administration suggest CGRP can act directly on the inner ear, which provides a basis for CGRP’s involvement in migraine with vertigo and as a therapeutic target.