Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation

Abstract

Over the past two decades, a convergence of basic and clinical evidence has established the neuropeptide calcitonin-gene-related peptide (CGRP) as a key player in migraine. Although CGRP is a recognised neuromodulator of nociception, its mechanism of action in migraine remains elusive. In this review, we present evidence that led us to propose that CGRP is well poised to enhance neurotransmission in migraine by both peripheral and central mechanisms. In the periphery, it is thought that local release of CGRP from the nerve endings of meningeal nociceptors following their initial activation by cortical spreading depression is critical for the induction of vasodilation, plasma protein extravasation, neurogenic inflammation and the consequential sensitisation of meningeal nociceptors. Mechanistically, we propose that CGRP release can give rise to a positive-feedback loop involved in localised increased synthesis and release of CGRP from neurons and a CGRP-like peptide called procalcitonin from trigeminal ganglion glia. Within the brain, the wide distribution of CGRP and CGRP receptors provides numerous possible targets for CGRP to act as a neuromodulator.

Figure 1. CGRP receptor in migraine

Schematic of the CGRP receptor complex composed of CLR, RAMP1 and RCP. Redrawn from Ref. with permission. Abbreviations: CGRP; calcitonin gene-related peptide; CLR, calcitonin-like receptor; RAMP1, receptor activity-modifying protein 1; RCP, receptor component protein.

Figure 2. Model of calcitonin gene-related peptide (CGRP)-induced hypersensitivity

Under normal conditions (top), CGRP levels are relatively low, leading to normal neurotransmission and proper filtering of sensory input. Migraine triggers initiate a transition to increased CGRP levels (bottom). The elevated CGRP levels increase synaptic transmission in the hypersensitive migraine brain. As a result, increased perception of sensory inputs is registered in the cortex as painful stimuli. Adapted from Ref. .

Figure 3. CGRP action at peripheral receptors

CGRP triggers an inflammatory cascade at the periphery. Inflammatory mediators released from mast cells sensitise sensory neurons and promote vascular permeability. Satellite glia influence the local microenvironment within the ganglia by releasing proinflammatory mediators such as tumour necrosis factor α (TNF-α), which can act on trigeminal neurons to increase CGRP synthesis and secretion, setting up a positive-feedback loop, which along with direct actions mediated by CGRP on a subset of trigeminal neurons might contribute to the extended duration of migraine. Satellite glia might also release proCT, which could also activate CGRP receptors.