Why Anti-CGRP Drugs Work for Migraine But Anti-Substance P Drugs Failed
Substance P is released in much smaller quantities than CGRP from migraine-relevant brain structures, explaining why blocking substance P receptors failed in clinical trials while anti-CGRP drugs succeeded.
Quick Facts
What This Study Found
Substance P release from stimulated dura mater, trigeminal ganglion neurons, and fibers was comparatively minor compared to CGRP release, explaining the clinical failure of NK1R antagonists for migraine while validating CGRP as the primary target.
Key Numbers
SP co-localizes with CGRP in C-fibers; SP release minor vs CGRP from dura, TG, and fibers; NKA in some C-fibers; NKB in large/medium neurons and A-delta fibers
How They Did This
Animal study using immunohistochemistry and semi-quantitative cell counts in rat trigeminal ganglia. Functional neuropeptide release measured by ELISA after stimulation with 60 mM potassium or 100 nM capsaicin.
Why This Research Matters
This resolves a decades-old mystery in migraine research: why blocking substance P didn't work. It validates the scientific rationale behind current anti-CGRP migraine drugs and clarifies substance P's limited role in migraine pain.
The Bigger Picture
Understanding the relative contributions of different neuropeptides to migraine helps explain why CGRP-targeting drugs (gepants and anti-CGRP antibodies) have been so successful. It also suggests that substance P might still play a role in migraine as a secondary amplifier, potentially relevant for treatment-resistant cases.
What This Study Doesn't Tell Us
Rat model — human trigeminal physiology may differ. In vitro stimulation conditions may not replicate natural migraine triggers. Release measurements are relative comparisons, not absolute quantification.
Questions This Raises
- ?Could targeting both CGRP and substance P simultaneously help patients who don't respond to anti-CGRP drugs alone?
- ?Does the substance P/CGRP release ratio differ in human trigeminal tissue compared to rats?
- ?What role does neurokinin B play in migraine given its different localization pattern?
Trust & Context
- Key Stat:
- SP << CGRP release Substance P release was comparatively minor versus CGRP from all migraine-relevant structures, explaining the failure of NK1R antagonists in clinical trials
- Evidence Grade:
- Moderate evidence: well-designed mechanistic animal study with functional release data, but uses rat tissue and in vitro stimulation rather than human or in vivo measurements.
- Study Age:
- Published in 2021. Anti-CGRP drugs have continued to show clinical success, further supporting this study's conclusions about CGRP dominance in migraine.
- Original Title:
- Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain.
- Published In:
- Molecular pain, 17, 17448069211059400 (2021)
- Authors:
- Edvinsson, Jacob Ca, Reducha, Philip V(2), Sheykhzade, Majid, Warfvinge, Karin, Haanes, Kristian A, Edvinsson, Lars
- Database ID:
- RPEP-05359
Evidence Hierarchy
Frequently Asked Questions
Why do anti-CGRP drugs work for migraine but substance P blockers don't?
This study shows that CGRP is released in much larger quantities than substance P from the nerves involved in migraine. Since CGRP is the dominant pain signal, blocking it is effective. Substance P plays only a minor supporting role, so blocking it alone doesn't provide meaningful relief.
Does substance P play any role in migraine?
Yes, but a secondary one. Substance P co-exists with CGRP in the same nerve fibers and may amplify pain signals. However, its release is much smaller than CGRP, which is why targeting substance P alone was insufficient for migraine treatment.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-05359APA
Edvinsson, Jacob Ca; Reducha, Philip V; Sheykhzade, Majid; Warfvinge, Karin; Haanes, Kristian A; Edvinsson, Lars. (2021). Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain.. Molecular pain, 17, 17448069211059400. https://doi.org/10.1177/17448069211059400
MLA
Edvinsson, Jacob Ca, et al. "Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain.." Molecular pain, 2021. https://doi.org/10.1177/17448069211059400
RethinkPeptides
RethinkPeptides Research Database. "Neurokinins and their receptors in the rat trigeminal system..." RPEP-05359. Retrieved from https://rethinkpeptides.com/research/edvinsson-2021-neurokinins-and-their-receptors
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.