Mechanism of Action
CLR/RAMP1 Receptor Complex
cgrp/" class="wiki-internal-link">CGRP acts via a heterodimeric receptor complex: calcitonin receptor-like receptor (CLR) paired with receptor activity-modifying protein 1 (RAMP1). This CLR/RAMP1 complex is Gs-coupled and highly expressed in vascular smooth muscle, trigeminal ganglion neurons, and dural blood vessels. CGRP binding activates adenylyl cyclase, increasing cAMP and causing potent, prolonged vasodilation. Adrenomedullin uses related receptor complexes, explaining some cross-pharmacology.
Migraine Pathophysiology
Trigeminal nerve activation in migraine releases CGRP from perivascular terminals in the dura mater, causing meningeal vasodilation, plasma protein extravasation (neurogenic inflammation), and activation of trigeminal pain pathways. CSF and plasma CGRP levels are elevated during migraine attacks and normalize with triptan treatment. Exogenous CGRP infusion provokes migraine in susceptible individuals, establishing causality.
Research Summary
Migraine Prevention (Anti-CGRP Antibodies)
FDA ApprovedFour anti-CGRP pathway monoclonal antibodies are FDA-approved for migraine prevention: erenumab (targets CGRP receptor), fremanezumab, galcanezumab, and eptinezumab (target CGRP ligand). Phase III trials show 40-50% reduction in monthly migraine days vs placebo in episodic and chronic migraine. These antibodies represent the first migraine-specific preventive medications and have transformed the field.
Gepants (Small Molecule CGRP Antagonists)
FDA ApprovedSmall molecule CGRP receptor antagonists (gepants) including rimegepant (Nurtec) and ubrogepant (Ubrelvy) are FDA-approved for acute migraine treatment. Atogepant (Qulipta) is approved for prevention. Gepants offer an oral alternative to triptans with a different mechanism and potentially better tolerability in patients with cardiovascular contraindications to triptans.
Cardiovascular and Pulmonary Roles
Preclinical/ResearchCGRP is cardioprotective during ischemia, promoting vasodilation and reducing infarct size in animal models. It is elevated in pulmonary arterial hypertension and heart failure as a compensatory vasodilator. Therapeutic CGRP supplementation for cardiovascular protection has been proposed but not clinically developed.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Migraine prevention (erenumab) | 70-140 mg SC monthly | Once monthly | Subcutaneous |
| Acute migraine (rimegepant) | 75 mg orally | As needed (max 1 per 24h) | Oral |
| CGRP-induced migraine provocation (research) | 1.5 ug/min IV infusion x 20 min | Single infusion | Intravenous |
Native CGRP is not administered therapeutically. The clinical benefit is achieved via antibody or small molecule CGRP pathway blockade. Anti-CGRP antibody use requires physician oversight and is indicated only for migraine prevention.
Interactions
Safety Profile
Anti-CGRP antibodies have excellent safety profiles in clinical trials: injection site reactions, constipation (erenumab), and mild nasopharyngitis. No hepatotoxicity (a concern that limited gepant development initially). Long-term safety data up to 5 years shows consistent tolerability. Cardiovascular safety monitoring is ongoing given CGRP's vasodilatory cardioprotective role. Gepants may cause constipation and somnolence. CGRP blockade during pregnancy is not recommended due to vasodilatory roles in placental circulation.
References
- [1]Amara SG, et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298(5871):240-244.
- [2]Goadsby PJ, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123-2132.
- [3]Durham PL. CGRP-receptor antagonists, a fresh approach to migraine therapy. N Engl J Med. 2004;350(11):1073-1075.