What CGRP stands for?
Calcitonin gene-related peptide (CGRP) is a neuropeptide (neurotransmitter of the nervous system) discovered more than 30 years ago. It has specific receptors located both centrally and in the periphery. CGRP is present in trigeminal neurons, and is released into the cranial venous outflow in acute migraine and cluster headache attacks.[1]
(Calcitonin gene related peptide) is produced in both central and peripheral neurons. It is a potent peptide vasodilator and can function in the transmission of nociception. It is derived mainly from the cell bodies of motor neurons when synthesized in ventral horn of the spinal cord and may contribute to the regeneration of nervous tissue after injury. Conversely, CGRP is derived from dorsal root ganglion when synthesized in the dorsal horn of the spinal cord and may be linked to the transmission of pain. In trigeminal vascular system cell bodies on the trigeminal ganglion are the main source of CGRP. It plays a role in cardiovascular homeostasis and nociception. It is also known to modulate the autonomic nervous system and play a role in ingestion. CGRP has been postulated to play an integral role in the pathophysiology of migraine. CGRP is released from trigeminal ganglia cells, and they are increased under conditions mimicking neurogenic inflammation. In migraine, activation of trigeminal nerves release CGRP and other peptides that cause the release of proinflammatory mediators. These mediators further increase CGRP synthesis and release over hours to days in correspondence with the 4-72 hour duration of a typical migraine episode. CGRP exists in two forms CGRP-1 and CGRP-2 and its family includes calcitonin, adrenomodullin, and amylin.
Functions
CGRP has several functions, such as:[2]
CGRP is primarily released from sensory nerves and thus is implicated in pain. Increased levels of CGRP have been reported in migraine, cluster headache, and might as well be present in temporomandibular disorders.[3]
Within the brain, CGRP increases with ischemia, injury, hyperthermia, and seizures, activating neuroprotective processes.[4]
The role of CGRP in pain management is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to peripheral and central pain sensitization (for example in migraine).[5]
CGRP as a target for pain management
The use of monoclonal antibodies against CGRP is a novel therapeutic strategy for the management of some painful conditions, such as migraine and cluster headache.[6]
CGRP-related therapies were designed specifically to act on the trigeminal pain system, with little or no adverse effects. Two groups of medications are available: the small molecule CGRP receptor antagonists (gepants) for acute relief of migraine headache, and the monoclonal antibodies against CGRP (Eptinezumab, Fremanezumab, and Galcanezumab) or the CGRP receptor (Erenumab) to prevent migraine attacks.[7]
Considering the comorbidity between migraine and TMD, and the role of CGRP in the trigeminal pain system, CGRP receptor antagonists may have therapeutic efficacy in the treatment of other facial pain conditions.[8] Understanding the pain mechanisms offers opportunities to develop therapeutic strategies with better chances to improve patient’s wellbeing.
[1] Edvinsson L. The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine. Headache. 2017 May;57 Suppl 2:47-55. doi: 10.1111/head.13081. PMID: 28485848.
[2] Russell, F. A., King, R., Smillie, S. J., Kodji, X., & Brain, S. D. (2014). Calcitonin gene-related peptide: physiology and pathophysiology. Physiological reviews, 94(4), 1099–1142.
[3] Yuan H, Spare NM, Silberstein SD. Targeting CGRP for the Prevention of Migraine and Cluster Headache: A Narrative Review. Headache. 2019 Jul;59 Suppl 2:20-32. doi: 10.1111/head.13583. PMID: 31291020.
[4] Borkum JM. CGRP and Brain Functioning: Cautions for Migraine Treatment. Headache. 2019 Sep;59(8):1339-1357. doi: 10.1111/head.13591. Epub 2019 Jul 21. PMID: 31328279.
[5] Yuan H, Lauritsen CG, Kaiser EA, Silberstein SD. CGRP Monoclonal Antibodies for Migraine: Rationale and Progress. BioDrugs. 2017 Dec;31(6):487-501. doi: 10.1007/s40259-017-0250-5. PMID: 29116598.
[6] Carmine Belin A, Ran C, Edvinsson L. Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache. Brain Sci. 2020 Jan 6;10(1):30. doi: 10.3390/brainsci10010030. PMID: 31935868; PMCID: PMC7016902.
[7] Edvinsson L. Role of CGRP in Migraine. Handb Exp Pharmacol. 2019;255:121-130. doi: 10.1007/164_2018_201. PMID: 30725283.
[8] Akerman S, Romero-Reyes M. Preclinical studies investigating the neural mechanisms involved in the co-morbidity of migraine and temporomandibular disorders: the role of CGRP. Br J Pharmacol. 2020 Dec;177(24):5555-5568. doi: 10.1111/bph.15263. Epub 2020 Oct 21. PMID: 32929719; PMCID: PMC7707098.
Durham P. L. (2006). Calcitonin gene-related peptide (CGRP) and migraine. Headache, 46 Suppl 1(Suppl 1), S3–S8. https://doi.org/10.1111/j.1526-4610.2006.00483.x