The signalling cascade from initial stimulus to downstream effector — and where therapeutic intervention is possible at each node.
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide predominantly expressed in trigeminal ganglion neurons, where it functions as a potent vasodilator and nociceptive modulator. During migraine attacks, activation of the trigeminovascular system — spanning trigeminal nerve fibres innervating the meningeal vasculature and their central projections — drives CGRP release into the cranial circulation and brainstem nuclei. Elevated CGRP levels are consistently detected in jugular venous blood during spontaneous migraine attacks, and exogenous CGRP infusion reliably triggers migraine-like attacks in susceptible individuals, establishing CGRP as a central mediator rather than mere epiphenomenon.
CGRP acts at its heterodimeric receptor (CGRP-R, comprising CLR and RAMP1 subunits) to produce dural vasodilation, facilitate neurogenic inflammation through mast cell and plasma protein extravasation, and sensitise trigeminal neurons — contributing to allodynia and central sensitisation. In chronic migraine, sustained CGRP pathway dysregulation promotes central sensitisation of second-order neurons in the trigeminal nucleus caudalis, lowering the threshold for future attacks. This peripheral and central sensitisation framework underpins the rationale for both acute and preventive CGRP-targeted therapies.
Anti-CGRP monoclonal antibodies developed for preventive use differ in their molecular targets: erenumab targets the CGRP receptor (CLR/RAMP1 complex), while fremanezumab, galcanezumab, and eptinezumab target the CGRP ligand itself. Monthly or quarterly dosing (eptinezumab administered intravenously quarterly) offers a significant adherence advantage over daily oral preventives. Gepants (rimegepant, atogepant) are small-molecule CGRP receptor antagonists that penetrate the CNS and are approved for both acute treatment and prevention, with the additional property of not causing medication overuse headache — a key distinguishing feature from triptans.
Upstream blockade vs downstream blockade — understanding the distinction is critical for treatment selection and sequencing.
Clinically actionable insights for treatment selection and sequencing
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide predominantly expressed in trigeminal ganglion neurons, where it functions as a potent vasodilator and nociceptive modulator.
During migraine attacks, activation of the trigeminovascular system — spanning trigeminal nerve fibres innervating the meningeal vasculature and their central projections — drives CGRP release into the cranial circulation and brainstem nuclei.
Elevated CGRP levels are consistently detected in jugular venous blood during spontaneous migraine attacks, and exogenous CGRP infusion reliably triggers migraine-like attacks in susceptible individuals, establishing CGRP as a central mediator rather than mere epiphenomenon.
CGRP acts at its heterodimeric receptor (CGRP-R, comprising CLR and RAMP1 subunits) to produce dural vasodilation, facilitate neurogenic inflammation through mast cell and plasma protein extravasation, and sensitise trigeminal neurons — contributing to allodynia and central sensitisation.
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