Headache peptide
Calcitonin gene-related peptide (CGRP)
Also searched as Calcitonin gene-related peptide (CGRP).
Four approved antibodies do nothing but block this one peptide or its receptor, and they prevent migraine. Rarely is a single molecule so cleanly implicated.
In depth
Calcitonin gene-related peptide — a potent vasodilator released from trigeminal nerve endings.
What drives it
Brain inflammation increases it.
CGRP previously had NO upstream edge at all, leaving migraine with a single unrooted driver. Verified at source: in acidic inflammatory environments, protons activate TRPV1 on sensory neurons; calcium entry activates calcium-calmodulin-dependent kinase, which phosphorylates CREB at Ser133; phospho-CREB binds cAMP response elements in the CGRP promoter and raises transcription (Mol Biol Cell doi 10.1091/mbc.e10-01-0049; Int J Mol Sci 2026 doi 10.3390/ijms27114973). TRPV1-deficient DRG showed reduced CGRP induction by acid, and a selective TRPV1 antagonist decreased it — loss-of-function both ways. Inflammatory mediators act in parallel: PGE2 raises CGRP and RAMP1 expression via EP4 and EP1/EP2 receptors, and COX-2 expression correlates positively with CGRP mRNA in human synovium (PMC5067902, n=43). This is a positive feedback loop, stated as such by the authors: CGRP further sensitizes nociceptors to subsequent noxious stimuli, raising CGRP again. Species: rat DRG and human synovial tissue. doi 10.1091/mbc.e10-01-0049 · PMC5067902
The Third Alarm Bell increases it.
PACAP and CGRP signaling converge on trigeminovascular activation; both provoke migraine on infusion and both are validated antibody targets. doi 10.1093/brain/awn307 · PMC10994530
What it drives
It increases Neurovascular calm.
CGRP is a 37-amino-acid peptide released from trigeminal neurons and a potent vasodilator, and its role in migraine is proven by the drug class built on it: four CGRP-targeted monoclonal antibodies are approved for migraine prevention — erenumab against the receptor, galcanezumab, fremanezumab and eptinezumab against the ligand — and all four have established efficacy (PMC9300070, PMC10811399, review PMC10586710). In the phase-2 randomized trial of one of them, monthly migraine days fell 4.2 versus 3.0 on placebo (p=0.003) with a 50% responder rate of 70% versus 45%. PMC9300070
It reduces Joint comfort.
CGRP is not only a migraine mediator: clinical and preclinical evidence associates it with hip and knee joint pain. In 43 patients with radiographic knee osteoarthritis (Kellgren/Lawrence grade 3-4) undergoing total knee arthroplasty, CGRP and COX-2 localized to the synovial lining layer and COX-2 expression correlated positively with CGRP mRNA; cultured synovial cells raised CGRP on PGE2 and EP4-agonist treatment, and RAMP1 on EP1/EP2 agonists (PMC5067902). Verified at source. this is joint pain, a symptom, not cartilage loss or structural progression — and the authors state the regulation mechanisms of CGRP signaling in synovial tissue are not fully understood. Human synovium, end-stage OA only. PMC5067902
It increases Calm pain signaling.
The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840
It increases Potassium channel gating.
The neuropeptides PACAP and CGRP activate KATP channels via the adenylyl cyclase pathway. doi 10.3390/cells11152406 · PMC10418850
It increases Trigeminal nerve pathway.
CGRP is released from trigeminal afferents and is the validated therapeutic target of the trigeminovascular pathway. doi 10.1177/03331024251355944 · PMC5567577
Blends that modulate it
Each blend page names this pathway and carries the study behind its claim.
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.