clinical topic updates

Calcitonin Gene-Related Peptide in the Pathogenesis of Migraine

by David W. Dodick, MD

Overview

Calcitonin gene-related peptide (CGRP) is an important neuropeptide in the pathogenesis of migraine. Whereas other neuropeptides in the trigeminal sensory nerve had been unsuccessfully targeted in the past, success with targeting CGRP has led to a number of US Food and Drug Administration approvals.

Expert Commentary

David W. Dodick, MD

Professor, Department of Neurology
Director, Concussion Program
Director, Headache Program
Mayo Clinic
Scottsdale, AZ

“When CGRP is released from C-fibers within the trigeminal nerve, it activates the CGRP receptors on Aδ-fibers, leading to signal propagation along the nerve. The signal then enters the brain, where it is registered as pain.”

David W. Dodick, MD

The trigeminal sensory nerve contains a whole host of neuropeptides and neurotransmitters, and some of these, such as substance P and neurokinin A, were targeted in the past, but to no avail. CGRP happens to be one of those neuropeptides, and success in targeting CGRP has led to several new treatments, including 4 monoclonal antibodies (mAbs; ie, eptinezumab, fremanezumab, galcanezumab, and erenumab) and the oral CGRP antagonists (ie, the gepants). 

When the trigeminal sensory system is activated, CGRP is released. When CGRP is released from C-fibers within the trigeminal nerve, it activates the CGRP receptors on Aδ-fibers, leading to signal propagation along the nerve. The signal then enters the brain, where it is registered as pain. This explains, in part, why these drugs are effective. We know that CGRP levels increase during a migraine and that those levels decrease when the migraine is effectively treated. We also know that when you block the peptide or its receptor, you get efficacy, whether in the acute or preventive setting. It is likely that gepants, which are now being used for acute treatment, may also become available for prevention at some point in the future. This would give patients the option of taking either a self-administered injection at monthly/quarterly intervals or an oral tablet once per day.

Interestingly, CGRP is also relevant to the efficacy of onabotulinumtoxinA in migraine. There are 2 different types of nerve fibers within the trigeminal nerve: C-fibers and Aδ-fibers. The C-fiber contains CGRP. OnabotulinumtoxinA inhibits the release of CGRP. Putting it all together, a CGRP receptor antagonist blocks a receptor that is located on the Aδ-fiber. And one of the mAbs also blocks the receptor while the others bind the ligand. So, we have botulinum toxin on the one hand preventing the release of CGRP, and then a gepant or one of the mAbs blocking the receptor. Perhaps that is why we are starting to see an enhanced effect when both onabotulinumtoxinA and anti-CGRP therapy are used, because they are working on the same pathway but in different nerve fibers.

Finally, we have learned that, although triptans were developed to constrict blood vessels, they actually bind to the trigeminal nerve and inhibit the release of neuropeptides and neurotransmitters. One of those neurotransmitters is CGRP. So, triptans actually inhibit the release of CGRP.

References

Barbanti P, Ferroni P. Onabotulinum toxin A in the treatment of chronic migraine: patient selection and special considerations. J Pain Res. 2017;10:2319-2329. doi:10.2147/JPR.S113614

Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019;394(10210):1765-1774. doi:10.1016/S0140-6736(19)32504-8

Deen M, Correnti E, Kamm K, et al; European Headache Federation School of Advanced Studies (EHF-SAS). Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain. 2017;18(1):96. doi:10.1186/s10194-017-0807-1

Edvinsson JCA, Warfvinge K, Krause DN, et al. C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. J Headache Pain. 2019;20(1):105. doi:10.1186/s10194-019-1055-3

Knight YE, Edvinsson L, Goadsby PJ. Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288. Neuropeptides. 1999;33(1):41-46. doi:10.1054/npep.1999.0009

Raffaelli B, Reuter U. The biology of monoclonal antibodies: focus on calcitonin gene-related peptide for prophylactic migraine therapy. Neurotherapeutics. 2018;15(2):324-335. doi:10.1007/s13311-018-0622-7

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