Role of CGRP and substance P in migraine.

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CGRP and Substance P in Migraine

Overview: The Trigeminovascular Theory

Migraine pain is best explained by the trigeminovascular theory proposed by Moskowitz. The trigeminal nerve and its unmyelinated C-fiber projections innervate intracranial and extracranial blood vessels. During a migraine attack, these fibers become activated, leading to the release of vasoactive neuropeptides - chiefly CGRP, substance P, and neurokinin A - from their nerve terminals into the perivascular space. This cascade drives vasodilation, neurogenic inflammation, and ultimately pain.

"Activation of these neurons releases nitric oxide and vasoactive peptides, such as calcitonin gene-related peptide (CGRP) and substance P, which then dilate intracranial blood vessels and induce local inflammatory reactions. Nociceptive signals originating from activation and sensitization of the trigeminovascular neurons are relayed to somatosensory cortex and other cortical areas, ultimately resulting in the perception of migraine pain." - Guyton and Hall Textbook of Medical Physiology

1. CGRP (Calcitonin Gene-Related Peptide)

Molecular Identity

CGRP is a 37-amino acid neuropeptide belonging to the calcitonin peptide family (along with calcitonin, adrenomedullin, and amylin). It exists in two isoforms in humans:

α-CGRP: derived from alternative splicing of the calcitonin/CGRP gene on chromosome 11; the principal form in migraine
β-CGRP: encoded by a separate gene in the same chromosomal region; differs by three amino acids

Its receptor is a G protein-coupled complex consisting of the calcitonin-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). Some effects are also mediated via the amylin-1 receptor (CTR + RAMP1). Both receptors are expressed throughout the CNS, cardiovascular system, and trigeminal ganglia.

Katzung's Basic and Clinical Pharmacology, 16th Edition

CGRP as the Most Potent Vasodilator

When injected systemically, CGRP causes hypotension, tachycardia, and positive inotropy - the hypotensive effect arising because CGRP is the most potent vasodilator yet discovered. It dilates multiple vascular beds (cutaneous, renal, coronary) by increasing nitric oxide production in endothelial cells, which relaxes underlying vascular smooth muscle.

Katzung's Basic and Clinical Pharmacology, 16th Edition

Role in Migraine Pathophysiology

CGRP has a central, well-established role:

Elevated during attacks: CGRP levels are measurably elevated in the internal jugular vein during acute migraine attacks. Treatment with sumatriptan normalizes these cranial CGRP levels.
Provocation model: Intravenous infusion of CGRP reliably triggers migraine-like headaches in migraineurs but not in controls - establishing a direct causal link.
Release from trigeminal terminals: Trigeminal nerve activation (via cortical spreading depression or other triggers) causes CGRP release into perivascular spaces of meningeal and cerebral vessels.
Vasodilation and sensitization: The released CGRP causes prolonged vasodilation of dural and intracranial arteries and sensitizes trigeminal nociceptors to mechanical stimuli (pulsation of vessels), which explains the throbbing quality of migraine pain.
Central sensitization: CGRP also acts centrally in the trigeminal nucleus caudalis and the thalamus, contributing to allodynia and central sensitization seen in severe migraine attacks.

"There has been a long-standing literature documenting a fundamental role for CGRP in the pathophysiology of migraine... elevated levels of CGRP can be measured in the internal jugular vein during an acute attack of migraine, which then normalize with treatment with sumatriptan. Further, experimental infusion of CGRP triggers migraine in patients with migraine but not controls." - Bradley and Daroff's Neurology in Clinical Practice

2. Substance P

Molecular Identity

Substance P is an 11-amino acid neuropeptide of the tachykinin family, co-localized with CGRP in trigeminal nerve terminals and widely distributed in the CNS, peripheral nervous system, and gut.

Katzung's Basic and Clinical Pharmacology, 16th Edition

Role in Migraine Pathophysiology

Substance P plays a complementary, inflammatory role to CGRP:

Co-released with CGRP: Upon trigeminal activation, substance P is released alongside CGRP and neurokinin A from perivascular nerve terminals onto meningeal blood vessels.
Promotes neurogenic inflammation: Substance P acts on NK-1 receptors on vascular endothelium and mast cells, causing:
- Plasma protein extravasation (vasodilation + increased permeability)
- Mast cell degranulation (releasing histamine, prostaglandins)
- Sterile inflammatory response in the dura mater
Mechanical sensitization: The perivascular edema from plasma extravasation mechanically stretches pain nerve endings in the dura - this mechanical stretch is believed to be an immediate cause of activation of dural nociceptors.
Central pain transmission: Substance P also functions as a neurotransmitter in the spinal trigeminal nucleus, facilitating pain signal transmission to higher centers.

"Activation of these fibers releases substance P, calcitonin gene-related peptide (CGRP), and other peptides into the vessel wall, which serves to sensitize the trigeminal system to the pulsatility of cranial vessels, and to increase their permeability, thereby promoting an inflammatory response." - Adams and Victor's Principles of Neurology, 12th Edition

"Extravasation of plasma and plasma proteins into the perivascular space appears to be a common feature of animal migraine models and is found in biopsy specimens from migraine patients. This effect probably reflects the action of the neuropeptides on the vessels. The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura." - Katzung's Basic and Clinical Pharmacology, 16th Edition

3. CGRP vs. Substance P: A Comparison

Feature	CGRP	Substance P
Type	37-amino acid peptide	11-amino acid tachykinin
Primary action	Potent vasodilation	Neurogenic inflammation / plasma extravasation
Receptor	CLR + RAMP1 (Gs-coupled)	NK-1 receptor
Role in migraine	Vasodilation, sensitization, central pain processing	Plasma extravasation, mast cell activation, dural inflammation
Plasma levels	Elevated in IJV during attacks	Elevated in dural perivascular space
Drug target	Yes - gepants (antagonists), anti-CGRP mAbs	Limited (NK-1 antagonists not effective in clinical trials)
Relative importance	Primary mediator	Secondary / modulatory

4. Other Neuropeptides in the Cascade

CGRP and substance P do not act alone. The full neuroinflammatory cascade also involves:

Neurokinin A (co-released with substance P, acts on NK-2 receptors)
Vasoactive intestinal polypeptide (VIP) - from parasympathetic cranial fibers
PACAP (pituitary adenylate cyclase-activating polypeptide) - another potent migraine trigger
Nitric oxide (NO) - released alongside CGRP from trigeminal terminals
Bradley and Daroff's Neurology in Clinical Practice; Lippincott Illustrated Reviews Pharmacology

5. Therapeutic Implications

The understanding of CGRP has directly driven a new class of migraine therapies:

A. Gepants (CGRP Receptor Antagonists)

Block the CLR/RAMP1 receptor complex
Ubrogepant and rimegepant - approved for acute migraine treatment
Rimegepant and atogepant - approved for migraine prevention
Vazgepant - intranasal gepant under investigation
First-generation gepants (olcegepant, telcagepant) were abandoned due to hepatotoxicity

B. Anti-CGRP Monoclonal Antibodies

Erenumab - targets the CGRP receptor (CLR/RAMP1 complex)
Fremanezumab and galcanezumab - target CGRP itself
Eptinezumab - also targets CGRP (IV formulation)
Used for preventive therapy, particularly in patients who have failed 2+ oral preventive agents

C. Triptans (5-HT1B/1D Agonists)

Indirectly suppress CGRP and substance P release by activating presynaptic 5-HT1D receptors on trigeminal terminals
Also cause vasoconstriction via 5-HT1B receptors on intracranial vessels
Normalize elevated CGRP levels during attacks

D. Botulinum Toxin (OnabotulinumtoxinA)

Approved for chronic migraine prophylaxis
Inhibits release of substance P, CGRP, and glutamate from trigeminal terminals

E. Anticonvulsants (e.g., gabapentin, pregabalin)

Decrease calcium influx, modulating release of substance P and other neuropeptides from trigeminal afferents
Katzung's Basic and Clinical Pharmacology, 16th Edition; Bradley and Daroff's Neurology in Clinical Practice; Lippincott Illustrated Reviews Pharmacology

Why Substance P Antagonists Failed Clinically

Despite the strong theoretical role of substance P, NK-1 receptor antagonists (e.g., lanepitant, GR205171) failed to show efficacy in clinical migraine trials. This likely reflects the greater dominance of CGRP in the human trigeminovascular system, and possibly species differences in the animal models that initially implicated substance P heavily. CGRP has since emerged as the primary molecular driver of migraine pain and the more clinically validated drug target.

Caution with CGRP Blockade

CGRP plays protective physiological roles in the cardiovascular system (vasodilation, counteracting renin-angiotensin activity, cardioprotection in hypertension/heart failure). Long-term blockade with monoclonal antibodies raises theoretical cardiovascular safety concerns - a caution explicitly flagged by Bradley and Daroff's Neurology in Clinical Practice. Post-marketing surveillance is ongoing.

Summary: CGRP is the master neuropeptide in migraine - released from trigeminal nerve terminals, it drives potent vasodilation and sensitizes meningeal nociceptors, with levels directly correlated to attack severity. Substance P amplifies the picture through neurogenic inflammation, plasma extravasation, and dural mast cell activation. The two peptides act synergistically within the trigeminovascular cascade, and CGRP has become the primary drug target for both acute and preventive migraine therapy.

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