Calcitonin gene-related peptide (CGRP) is a 37-aa neuropeptide released from trigeminal sensory afferents → vasodilation + neurogenic inflammation in the meningeal vasculature. Validated migraine target: CGRP elevation during migraine attack; IV CGRP triggers migraine in susceptible patients. Two therapeutic classes: (1) Small-molecule CGRP-R antagonists (gepants — rimegepant, ubrogepant, atogepant) for acute treatment + prophylaxis; (2) Biologics — anti-CGRP mAbs (fremanezumab, galcanezumab, eptinezumab) or anti-CGRP-R mAb (erenumab) for prevention. Triptans (sumatriptan, rizatriptan — covered in serotonin pathway) work upstream via 5-HT1B/1D agonism that reduces CGRP release; the two classes are complementary but mechanistically linked. Long-term CGRP blockade safety is being monitored (CGRP has physiologic vasodilator role in cardiac stress response).
Organ Systems
nervous
cardiovascular
Pathway Steps
trigeminal-sensory-afferent → cgrp-release — via activation in meningeal sensory fibers → CGRP secretion → vasodilation + inflammation. Activation of trigeminal sensory afferents innervating the meninges releases calcitonin gene-related peptide (CGRP), a potent neuropeptide central to migraine. Elevated CGRP during attacks made it the defining target of modern migraine therapeutics.
cgrp-release → meningeal-vasodilation — via CGRP-R on smooth muscle + perivascular nerves → vasodilation + pain transmission. Released CGRP causes meningeal vasodilation and neurogenic inflammation and sensitizes pain pathways, generating the headache. Blocking it — anti-CGRP/receptor antibodies (erenumab) or small-molecule “gepants” — both prevents and treats migraine, validating the axis.
Known Modulators
rimegepant (inhibitor) — CGRP receptor. gepant; oral disintegrating tablet; both acute migraine (75 mg PRN) + preventive (75 mg every other day); CYP3A4 substrate