CGRP (Calcitonin Gene-Related Peptide)

CGRP (Calcitonin Gene-Related Peptide) is a 37-amino acid neuropeptide that exists in two forms: α-CGRP (predominantly expressed in sensory neurons) and β-CGRP (primarily found in enteric neurons). α-CGRP is produced by alternative splicing of the calcitonin gene (CALCA) and is abundantly expressed in trigeminal sensory neurons, dorsal root ganglia, and perivascular nerve fibers. CGRP is one of the most potent endogenous vasodilators known, with effects lasting hours compared to the transient vasodilation of other mediators.

CGRP acts through a heterodimeric receptor complex consisting of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). This receptor complex is expressed on vascular smooth muscle, meningeal arteries, trigeminal nucleus caudalis neurons, and other sites relevant to migraine pathophysiology. CGRP receptor activation leads to cAMP accumulation, vasodilation, neurogenic inflammation, and sensitization of trigeminal pain pathways.

The role of CGRP in migraine was established through several key observations: CGRP levels increase in the external jugular vein during migraine attacks, intravenous CGRP infusion triggers migraine in susceptible individuals, and triptans (effective migraine treatments) reduce CGRP levels. These findings led to one of the most successful targeted drug development programs in recent pharmaceutical history.

CGRP-targeted therapies now include monoclonal antibodies against CGRP itself (fremanezumab/Ajovy, galcanezumab/Emgality, eptinezumab/Vyepti) and against the CGRP receptor (erenumab/Aimovig), as well as small-molecule CGRP receptor antagonists ("gepants") for both acute treatment (ubrogepant/Ubrelvy, rimegepant/Nurtec ODT) and prevention. This class of medications has transformed migraine treatment by providing targeted, mechanism-based therapy with favorable safety profiles compared to older preventive medications.

Beyond migraine, CGRP has roles in cardiovascular protection (vasodilation, prevention of vascular remodeling), wound healing, and metabolic regulation. Concerns about the long-term cardiovascular safety of sustained CGRP blockade have been largely alleviated by clinical trial and post-marketing data, though surveillance continues.