Loss of α-Calcitonin Gene-Related Peptide (αCGRP) Reduces Otolith Activation Timing Dynamics and Impairs Balance

This review considers whether the vestibular system includes separate populations of sensory axons innervating individual organs and giving rise to distinct central pathways. There is a variability in the discharge properties of afferents supplying each organ. Discharge regularity provides a marker for this diversity since fibers which differ in this way also differ in many other properties. Postspike recovery of excitability determines the discharge regularity of an afferent and its sensitivity to depolarizing inputs. Sensitivity is small in regularly discharging afferents and large in irregularly discharging afferents. The enhanced sensitivity of irregular fibers explains their larger responses to sensory inputs, to efferent activation, and to externally applied galvanic currents, but not their distinctive response dynamics. Morphophysiological studies show that regular and irregular afferents innervate overlapping regions of the vestibular nuclei. Intracellular recordings of EPSPs reveal that some secondary vestibular neurons receive a restricted input from regular or irregular afferents, but that most such neurons receive a mixed input from both kinds of afferents. Anodal currents delivered to the labyrinth can result in a selective and reversible silencing of irregular afferents. Such a functional ablation can provide estimates of the relative contributions of regular and irregular inputs to a central neuron's discharge. From such estimates it is concluded that secondary neurons need not resemble their afferent inputs in discharge regularity or response dynamics. Several suggestions are made as to the potentially distinctive contributions made by regular and irregular afferents: (1) Reflecting their response dynamics, regular and irregular afferents could compensate for differences in the dynamic loads of various reflexes or of individual reflexes in different parts of their frequency range; (2) The gating of irregular inputs to secondary VOR neurons could modify the operation of reflexes under varying behavioral circumstances; (3) Two-dimensional sensitivity can arise from the convergence onto secondary neurons of otolith inputs differing in their directional properties and response dynamics; (4) Calyx afferents have relatively low gains when compared with irregular dimorphic afferents. This could serve to expand the stimulus range over which the response of calyx afferents remains linear, while at the same time preserving the other features peculiar to irregular afferents. Among those features are phasic response dynamics and large responses to efferent activation; (5) Because of the convergence of several afferents onto each secondary neuron, information transmission to the latter depends on the gain of individual afferents, but not on their discharge regularity.

Migraine is a highly prevalent neurovascular disorder that can be provoked by infusion of calcitonin gene-related peptide (CGRP). CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates intracranial and extracranial blood vessels and centrally modulates vascular nociception. On this basis, it has been proposed that: (i) CGRP may play an important role in the pathophysiology of migraine; and (ii) blockade of CGRP receptors may abort migraine. With the advent of potent and selective CGRP receptor antagonists, the importance of CGRP in the pathophysiology of migraine and the therapeutic principle of CGRP receptor antagonism were clearly established. Indeed, both olcegepant (BIBN4096BS, given intravenously) and telcagepant (MK-0974, given orally) have been shown to be safe, well tolerated and effective acute antimigraine agents in phase I, phase II, and for telcagepant phase III, studies. However, recent data reported elevated liver transaminases when telcagepant was dosed twice daily for three months for the prevention of migraine rather than acutely. The potential for a specific acute antimigraine drug, without producing vasoconstriction or vascular side effects and with an efficacy comparable to triptans, is enormous. The present review will discuss the role of CGRP in the pathophysiology of migraine and the various treatment modalities that are currently available to target this neuropeptide.

Vestibular migraine is becoming recognised as a distinct clinical entity that accounts for a high proportion of patients with vestibular symptoms. A temporal overlap between vestibular symptoms, such as vertigo and head-movement intolerance, and migraine symptoms, such as headache, photophobia, and phonophobia, is a requisite diagnostic criterion. Physical examination and laboratory testing are usually normal in vestibular migraine but can be used to rule out other vestibular disorders with overlapping symptoms. The pathophysiology of vestibular migraine is incompletely understood but plausibly could include neuroanatomical pathways to and from central vestibular structures and neurochemical modulation via the locus coeruleus and raphe nuclei. In the absence of controlled trials, treatment options for patients with vestibular migraine largely mirror those for migraine headache. Copyright © 2013 Elsevier Ltd. All rights reserved.