Activation and sensitization of meningeal nociceptors by PACAP-38: implications for migraine headache
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By
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Rune Häckert Christensen
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Andrew Strassman
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Messoud Ashina
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Håkan Ashina
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Rami Burstein
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August 6, 2025
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Clinical Scorecard: Activation and Sensitization of Meningeal Pain Receptors by PACAP-38: Consequences for Migraine Headaches
At a Glance
| Category | Detail |
|---|
| Condition | Migraine and other headache disorders |
| Key Mechanisms | Peripheral activation and sensitization of meningeal nociceptors by PACAP-38 |
| Target Population | People with migraine and healthy adults |
| Care Setting | Neurology and headache specialty clinics; research settings |
Key Highlights
- Systemic infusion of PACAP-38 induces migraine headache in migraineurs and mild headache in healthy adults.
- PACAP-38 activates both C-fibre and Aδ-fibre meningeal nociceptors in the trigeminal ganglion.
- Peripheral blockade of PACAP reduces migraine frequency, suggesting peripheral mechanisms predominate.
Guideline-Based Recommendations
Diagnosis
- Consider involvement of meningeal nociceptor activation in migraine pathophysiology.
Management
- Target peripheral PACAP pathways for migraine treatment, as monoclonal antibodies blocking PACAP reduce migraine days.
- Use dosing regimens that mimic clinical PACAP-38 infusion protocols for experimental migraine induction.
Monitoring & Follow-up
- Monitor headache frequency and severity in response to PACAP-targeted therapies.
Risks
- Potential for PACAP-38 to induce headache via peripheral nociceptor activation.
Patient & Prescribing Data
Patients with migraine
Monoclonal antibodies targeting PACAP ligand reduce monthly migraine days, supporting peripheral PACAP blockade as an effective strategy.
Clinical Best Practices
- Recognize the role of meningeal nociceptors in migraine pathogenesis.
- Consider peripheral PACAP-38 activation as a therapeutic target.
- Use electrophysiological and mechanical stimulation assessments in research to evaluate nociceptor activation.
References
