What neuropeptides are involved in migraine?

Neuropeptides Involved in Migraine

Primary Neuropeptide: Calcitonin Gene-Related Peptide (CGRP)

CGRP is the most clinically significant neuropeptide in migraine pathophysiology, with robust evidence demonstrating its release during migraine attacks, its ability to trigger migraine when administered to patients, and the clinical success of CGRP-targeting therapies in both acute and preventive migraine treatment. 1, 2

Evidence for CGRP's Role

• CGRP levels are elevated in blood samples during migraine attacks, and effective triptan treatment normalizes these levels 1, 2
• Intravenous CGRP administration triggers headache in migraine patients, establishing causality 1, 2
• CGRP is widely distributed in migraine-relevant anatomical areas, particularly the trigeminovascular nociceptive system 2, 3
• CGRP receptor antagonists (gepants) and CGRP-neutralizing monoclonal antibodies successfully abort and prevent migraine attacks 1, 4, 2

Clinical Translation of CGRP Targeting

• The American College of Physicians recommends CGRP monoclonal antibodies (fremanezumab, galcanezumab, eptinezumab) for prevention of episodic or chronic migraine 4, 5
• CGRP receptor antagonists (rimegepant, ubrogepant, zavegepant) are FDA-approved for acute episodic migraine treatment 1, 4
• CGRP-targeting therapies represent the only unambiguous pain drug development success story in recent decades 1

Secondary Neuropeptide: Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)

PACAP has emerged as an alternative therapeutic target, acting through largely independent pathways from CGRP and potentially explaining why approximately 50% of patients do not respond adequately to CGRP-targeted therapies. 6

PACAP's Distinct Role

• PACAP shares similarities with CGRP but is more prominent in parasympathetic ganglia, contributing to autonomic aspects of migraine 6, 7
• PACAP induces similar migraine-like behaviors in preclinical models (mechanical allodynia, photophobia, non-evoked pain) but through pathways not blocked by CGRP-targeted therapies 6
• PACAP activates overlapping but distinct intracellular signaling pathways compared to CGRP, being more effective at engaging alternative cAMP pathways and Gq-mediated calcium pathways 6
• PACAP and CGRP likely act by parallel and non-redundant roles in migraine pathophysiology 6, 7

Additional Neuropeptides in the Trigeminovascular System

Sensory Neuropeptides

• Substance P (SP): Released from activated peripheral nociceptive sensory nerve terminals (C and A-delta fibers), leading to arteriolar vasodilation, plasma protein extravasation, and mast cell degranulation 7, 8
• Neurokinin A: Works alongside substance P in neurogenic inflammation, with antidromic stimulation of trigeminal nerve fibers resulting in marked plasma protein extravasation from dural blood vessels 7, 8

Autonomic Neuropeptides

• Vasoactive Intestinal Peptide (VIP): A parasympathetic neuropeptide involved in the trigeminovascular system 7
• Neuropeptide Y (NPY): A sympathetic neuropeptide with functions in the trigeminovascular system 7

Modulatory Neuropeptides

• Somatostatin: Plays a functional role in the trigeminovascular system 7
• Nociceptin: Involved in trigeminovascular system modulation 7
• Orexins: Participate in trigeminovascular system function 7

Mechanism of Neurogenic Inflammation

• Neuropeptides contribute to neurogenic inflammation through plasma protein extravasation and vasodilation of intracranial vasculature 7, 8
• These processes lead to peripheral and central sensitization of the trigeminal system 7, 8
• Clinically effective antimigraine medications (ergots, triptans) attenuate neuropeptide release and neurogenic plasma protein extravasation 8

Clinical Implications

• CGRP remains the primary therapeutic target with proven clinical efficacy, while PACAP represents a promising future target for patients who do not respond to CGRP-targeted therapies 6
• Combined targeting of CGRP and PACAP may offer a more effective strategy for treating migraine, given their parallel and non-redundant pathophysiological roles 6
• The involvement of multiple neuropeptides explains the heterogeneity of migraine presentation and variable treatment responses across patients 3, 6, 7