Trigeminal Activation And CGRP Release
Trigeminal nerve fibers release CGRP during migraine onset.
- ~7 min: CGRP plasma half-life (rapid clearance from blood)
- ~100k: Trigeminal ganglion neurons (sensory neurons per side)
- High: CGRP receptor density (on vascular smooth muscle)
- 1983: CGRP discovery (peptide first identified)
Peptide synthesis
Sensory neurons synthesize CGRP in trigeminal ganglion cell bodies.
Axonal release
Nerve depolarization triggers vesicle fusion and peptide release.
Perivascular spread
Released CGRP diffuses toward nearby meningeal blood vessels.
CGRP Receptor Binding And Neurogenic Inflammation
CGRP binding dilates vessels and sensitizes pain fibers.
- ~20-30%: Vessel diameter increase (meningeal artery dilation)
- CLR/RAMP1: Receptor type (canonical CGRP receptor complex)
- Rapid: Pain sensitization onset (minutes after CGRP binding)
- ~1 billion: Migraine prevalence (people affected worldwide)
Receptor complex
CGRP binds CLR-RAMP1 receptor complexes on vessel walls.
cAMP signaling
Receptor activation raises cAMP, relaxing vascular smooth muscle.
Neurogenic inflammation
Inflammation and dilation together generate throbbing migraine pain.
Monthly Injection Delivers Anti-CGRP Antibody
A subcutaneous injection introduces engineered anti-CGRP antibodies.
- 4: Approved CGRP mAbs (erenumab, fremanezumab, galcanezumab, eptinezumab)
- ~28 days: Antibody half-life (supports monthly dosing schedule)
- Subcutaneous: Administration route (self-injected at home monthly)
- 2018: First mAb approval (erenumab approved by FDA)
Engineered antibodies
Humanized antibodies target CGRP peptide or its receptor.
Systemic circulation
Antibody circulates in blood, staying outside the brain.
Selective targeting
High specificity limits binding to unrelated peptide receptors.
Antibody Neutralizes The CGRP Signaling Pathway
Antibodies capture CGRP or block its receptor directly.
- 2 types: Blockade strategies (ligand-binding or receptor-binding mAb)
- Receptor: Erenumab target (blocks CGRP receptor directly)
- Ligand: Fremanezumab target (neutralizes free CGRP peptide)
- Sustained: Blockade duration (persists between monthly doses)
Ligand-targeting antibodies
Fremanezumab and galcanezumab bind and neutralize free CGRP.
Receptor-targeting antibody
Erenumab occupies the CGRP receptor, blocking peptide access.
Downstream effect
Blocked signaling prevents vasodilation and nociceptor sensitization.
Sustained Blockade Lowers Monthly Migraine Days
Continuous treatment steadily reduces monthly migraine burden.
- ~50%: Migraine day reduction (patients see halved monthly days)
- Weeks 1-4: Response onset (early clinical improvement observed)
- Common: Chronic-to-episodic shift (with sustained antibody therapy)
- 12 months: Long-term trial length (typical efficacy study duration)
Early response
Many patients respond within the first treatment month.
Cumulative benefit
Migraine days keep declining across months of therapy.
Quality of life
Fewer migraine days improve daily function and productivity.