Calcitonin gene-related peptide (CGRP): a new target for migraine

Abstract

Migraine is a neurological disorder that manifests as a debilitating headache associated with altered sensory perception. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. Clinical trials carried out during the past decade have proved that CGRP receptor antagonists are effective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation. Despite this progress in the clinical arena, the mechanisms by which CGRP triggers migraine remain uncertain. This review discusses mechanisms whereby CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Future studies on epistatic and epigenetic regulators of CGRP actions are expected to shed further light on CGRP actions in migraine. In conclusion, targeting CGRP represents an approachable therapeutic strategy for migraine.

Keywords: neuromodulation; neuropeptide; photophobia; sensitization; trigeminovasculature.

Figure 1

Trigeminovascular system. Primary afferents of neurons in the trigeminal ganglion extend from the meningeal vasculature to central terminals in the TNC (brown). Second-order neurons of the TNC, in turn, project to the posterior thalamus. The SPG (purple) also provides reflex parasympathetic innervation to meningeal vessels. Abbreviations: SPG, sphenopalatine ganglion; TNC, trigeminal nucleus caudalis. Figure adapted from Reference 31 with permission; originally adapted from Reference 1.

Figure 2

CGRP and its receptor. (a) Human α-CGRP sequence with an amidated C terminus and N-terminal disulfide bond, indicated by the bracket. (b) The CGRP receptor complex, which contains three subunits: CLR, RAMP1, and RCP. Abbreviations: CGRP, calcitonin gene-related peptide; CLR, calcitonin-like receptor; RAMP1, receptor activity-modifying protein 1; RCP, receptor component protein.

Figure 3

CGRP-induced hypersensitivity to sensory stimuli. (a) Under normal conditions, CGRP levels are relatively low, neurotransmission is normal, and sensory input is properly filtered. Triggers of migraine lead to an increase in CGRP levels (b), causing enhanced synaptic transmission and thereby pain and altered sensory perception. Abbreviation: CGRP, calcitonin gene-related peptide. Figure modified from Reference 19 with permission; originally adapted from Reference 48.

Figure 4

CGRP facilitates synaptic transmission as a neuromodulator of glutamate release and receptor activation. CGRP (red circles) released from presynaptic terminals (light blue) leads to additional release of glutamate (brown circles) and CGRP. At postsynaptic terminals (dark blue), CGRP increases neuronal excitability by cAMP-dependent phosphorylation of AMPARs and NMDARs, leading to increased conductance and synaptic facilitation. In addition, neuronal CGRP may act in a paracrine fashion on nearby glia (yellow) and dural mast cells (not shown) to indirectly influence the neurons. Abbreviations: AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; cAMP, cyclic adenosine monophosphate; CGRP, calcitonin gene-related peptide; CLR, calcitonin-like receptor; NMDAR, N-methyl-d-aspartate receptor; RAMP1, receptor activity-modifying protein re modified from Reference 58 with permission.