CGRP actions relevant to migraine pathogenesis

Abstract

Migraine is a common neurological disorder characterized by recurrent headache attacks of moderate to severe intensity. Accumulating evidence indicates that calcitonin gene–related peptide (CGRP) plays a pivotal role in migraine pathogenesis. CGRP–based pharmacological interventions are already in clinical use worldwide. CGRP–induced sensitization of the trigeminal system seems to be an important event for migraine headache generation. In the dura, CGRP expression is found in unmyelinated C–fibers, whereas the CGRP receptor components, CLR and RAMP1, are expressed in myelinated Aδ–fibers. Upon activation of the CGRP receptor, a cascade of intracellular events is provoked within the trigeminal ganglion neurons, including altered transcriptional activity, nitric oxide synthase activation and the post–translational modifications of receptors and ion channels. Moreover, CGRP–induced activation of satellite glial cells can drive inflammatory processes through the production of proinflammatory cytokines and nitric oxide. All these phenomena contribute to the development of trigeminal sensitization. CGRP–related antibodies are known to reach the dura and the trigeminal ganglia. CGRP and its receptors are also expressed in the central nervous system. Notably, CGRP expression is observed within the projections from the parabrachial nucleus to the central amygdala. This pathway is closely related to nocifensive reactions and provocation of unpleasant memories associated with past migraine attacks. It is obvious that CGRP exerts multifaceted actions in migraine disease mechanism.