Systemic calcitonin gene-related peptide modifies auditory and vestibular end organ electrical potentials, and increases sensory hypersensitivities

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 whether exogenous CGRP can modulate inner ear function at the end organ level and cause heightened behavioral responses consistent with VM. We tested whether intraperitoneally (ip) delivered CGRP to wild-type 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 intraperitoneal CGRP, and observed that female mice exhibited heightened sensitivities to intraperitoneal 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 patients with VM.<b>NEW & NOTEWORTHY</b> Calcitonin 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 whether increases in systemic CGRP can act directly on inner ear end organs. In this study, we determined systemic CGRP changes auditory (ABR) and vestibular (VsEP) endorgan potentials and produces migraine behaviors similar to phonophobia and postural control deficits.