View source for Calcitonin gene-related peptide

{{Short description|Peptide hormone in animals}}
{{infobox protein
| Name       = [[Calcitonin|Calcitonin-related polypeptide alpha]]
| caption    = Human calcitonin (black) bound to the [[calcitonin receptor]]. {{PDB|7TYO}}
| image      = Human calcitonin bound to receptor PDB 7TYO.png
| width      = 173
| HGNCid     = 1437
| Symbol     = [[Calcitonin|CALCA]]
| AltSymbols = CALC1
| EntrezGene = 796
| OMIM       = 114130
| RefSeq     = NM_001741
| UniProt    = P06881
| PDB        = 
| ECnumber   = 
| Chromosome = 11
| Arm        = p
| Band       = 15.2
}}
{{infobox protein
| Name       = Calcitonin-related polypeptide, beta
| caption    = 
| image      = 
| width      = 
| HGNCid     = 1438
| Symbol     = CALCB
| AltSymbols = CALC2
| EntrezGene = 797
| OMIM       = 114160
| RefSeq     = NM_000728
| UniProt    = P10092
| PDB        = 
| ECnumber   = 
| Chromosome = 11
| Arm        = p
| Band       = 15.2
}}

'''Calcitonin gene-related peptide''' ('''CGRP''') is a [[neuropeptide]] that belongs to the [[calcitonin]] family.<ref>{{Cite journal |last=Russell |first=F. A. |last2=King |first2=R. |last3=Smillie |first3=S.-J. |last4=Kodji |first4=X. |last5=Brain |first5=S. D. |date=October 2014 |title=Calcitonin Gene-Related Peptide: Physiology and Pathophysiology |url=https://journals.physiology.org/doi/full/10.1152/physrev.00034.2013 |journal=Physiological Reviews |volume=94 |issue=4 |pages=1099–1142 |doi=10.1152/physrev.00034.2013 |issn=0031-9333 |pmc=4187032 |pmid=25287861}}</ref> Human CGRP consists of two [[Protein isoform|isoforms]], CGRP alpha (α-CGRP, also known as CGRP I) and CGRP beta (β-CGRP, also known as CGRP II).<ref name="Calcitonin gene-related peptide: ph">{{cite journal | vauthors = Russell FA, King R, Smillie SJ, Kodji X, Brain SD | title = Calcitonin gene-related peptide: physiology and pathophysiology | journal = Physiological Reviews | volume = 94 | issue = 4 | pages = 1099–142 | date = October 2014 | pmid = 25287861 | pmc = 4187032 | doi = 10.1152/physrev.00034.2013 }}</ref> α-CGRP is a 37-[[amino acid]] neuropeptide formed by [[alternative splicing]]<ref>{{cite journal | vauthors = Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM | title = Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products | journal = Nature | volume = 298 | issue = 5871 | pages = 240–4 | date = July 1982 | pmid = 6283379 | doi = 10.1038/298240a0 | s2cid = 24188834 | bibcode = 1982Natur.298..240A }}</ref> of the calcitonin/CGRP gene located on [[chromosome 11]]. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene.<ref name="pmid19062206">{{cite journal | vauthors = Rezaeian AH, Isokane T, Nishibori M, Chiba M, Hiraiwa N, Yoshizawa M, Yasue H | title = alphaCGRP and betaCGRP transcript amount in mouse tissues of various developmental stages and their tissue expression sites | journal = Brain & Development | volume = 31 | issue = 9 | pages = 682–93 | date = October 2009 | pmid = 19062206 | doi = 10.1016/j.braindev.2008.10.011 | s2cid = 21635386 }}</ref> The CGRP family includes calcitonin (CT), [[adrenomedullin]] (AM), and [[amylin]] (AMY).<ref>{{cite journal | vauthors = Edvinsson L | title = The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine | journal = Headache | volume = 57 Suppl 2 | issue = S2 | pages = 47–55 | date = May 2017 | pmid = 28485848 | doi = 10.1111/head.13081 | doi-access = free }}</ref>

== Function ==
CGRP is produced in both peripheral and central [[neuron]]s.<ref name="pmid6346105">{{cite journal | vauthors = Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM | display-authors = 6 | title = Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing | journal = Nature | volume = 304 | issue = 5922 | pages = 129–35 | year = 1983 | pmid = 6346105 | doi = 10.1038/304129a0 | bibcode = 1983Natur.304..129R | s2cid = 4322278 }}</ref> It is a potent peptide [[vasodilator]] and can function in the transmission of [[nociception]].<ref name="pmid3917554">{{cite journal | vauthors = Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I | title = Calcitonin gene-related peptide is a potent vasodilator | journal = Nature | volume = 313 | issue = 5997 | pages = 54–6 | year = 1985 | pmid = 3917554 | doi = 10.1038/313054a0 | bibcode = 1985Natur.313...54B | s2cid = 4329128 }}</ref><ref name="pmid3488550">{{cite journal | vauthors = McCulloch J, Uddman R, Kingman TA, Edvinsson L | title = Calcitonin gene-related peptide: functional role in cerebrovascular regulation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 15 | pages = 5731–5 | date = August 1986 | pmid = 3488550 | pmc = 386363 | doi = 10.1073/pnas.83.15.5731 | bibcode = 1986PNAS...83.5731M | doi-access = free }}</ref> In the [[spinal cord]], the function and expression of CGRP may differ depending on the location of synthesis. CGRP is derived mainly from the cell bodies of [[motor neuron]]s when synthesized in the [[Ventral horn of spinal cord|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]].<ref name="pmid19969463">{{cite journal | vauthors = Chen LJ, Zhang FG, Li J, Song HX, Zhou LB, Yao BC, Li F, Li WC | display-authors = 6 | title = Expression of calcitonin gene-related peptide in anterior and posterior horns of the spinal cord after brachial plexus injury | journal = Journal of Clinical Neuroscience | volume = 17 | issue = 1 | pages = 87–91 | date = January 2010 | pmid = 19969463 | doi = 10.1016/j.jocn.2009.03.042 | s2cid = 29249307 }}</ref> In the trigeminal vascular system, the cell bodies of the [[trigeminal ganglion]] are the main source of CGRP. CGRP is thought to play a role in cardiovascular homeostasis and nociception. In the heart, CGRP acts as a [[chronotrope]] by increasing [[heart rate]].<ref name="Norman_2014">{{Cite book |title=Hormones | vauthors = Norman A, Henry H, Litwack G |publisher=Elsevier |year=2014 |isbn=978-0-12-369444-7|location= Amsterdam }}</ref>{{rp|202}} Apart from these attributes, CGRP is known to modulate the [[autonomic nervous system]] and plays a role in ingestion.<ref name="Norman_2014" />{{rp|201–204}}

CGRP has moderate effects on calcium homeostasis compared to its extensive actions in other areas, such as the autonomic nervous system.

=== Appetite ===
As a neuropeptide, CGRP acts as an [[appetite suppressant]] and contributes to [[gastric acid]] secretion.<ref name="Norman_2014" /> It also functions in [[temperature homeostasis]], increases heart rate, and plays a role in the release of the [[pituitary hormones]] in a [[paracrine]] manner.<ref name="Norman_2014" /> Because of these characteristics, it has been said that CGRP functions more as a [[neurotransmitter]] than a hormone.<ref name="Norman_2014" />

=== Stem cell mobilization ===
CGRP has a role in human [[stem cell]] (HSC) mobilization.<ref>{{Cite journal |last2= Chen|first2= Qingquan|last3= Zhang|first3= Shuyu|last4= Gao|first4= Feng|last5= Liu|first5= Qicai|date=2022-01-29 |title=CGRP: A New Endogenous Cell Stemness Maintenance Molecule |journal=Oxidative Medicine and Cellular Longevity |volume=2022 |pages=4107433 |doi=10.1155/2022/4107433 |doi-access= free|issn=1942-0900 |pmc=8817839 |pmid=35132349|last1= Lv|first1= Xiaoting}}</ref> In investigations carried out in 2021, treatment with CGRP resulted in significantly increased CGRP levels in the [[bone marrow]] extracellular fluid and substantially increased the number of HSCs mobilized by [[granulocyte colony-stimulating factor]] (G-CSF).<ref name="Gao_2021">{{cite journal | vauthors = Gao X, Zhang D, Xu C, Li H, Caron KM, Frenette PS | title = Nociceptive nerves regulate haematopoietic stem cell mobilization | journal = Nature | volume = 589 | issue = 7843 | pages = 591–596 | date = January 2021 | pmid = 33361809 | pmc = 7856173 | doi = 10.1038/s41586-020-03057-y | bibcode = 2021Natur.589..591G }}</ref> The authors of the 2021 study concluded that G-CSF-induced HSC mobilization is regulated by the nociceptor nerve-derived neuropeptide CGRP. This peptide exerts its effect on HSC mobilization via the [[Receptor activity-modifying protein|receptor activity-modifying protein 1]] (RAMP1) pathway.<ref name="Gao_2021" />

== Receptors ==
[[File:Human calcitonin recptor-Gs complex PDB 7TYO.png|thumb|Structure of the human calcitonin receptor-Gs complex. The calcitonin transmembrane receptor (blue) is bound to human calcitonin (red) and the G<sub>s</sub> complex (yellow). {{PDB|7TYO}}]]
CGRP mediates its effects through a [[heteromeric]] receptor composed of a [[G protein-coupled receptor]] called calcitonin receptor-like receptor ([[CALCRL]]) and RAMP1.<ref name="pmid12037140">{{cite journal | vauthors = Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM | s2cid = 17302944 | display-authors = 6 | title = International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors | journal = Pharmacological Reviews | volume = 54 | issue = 2 | pages = 233–46 | date = June 2002 | pmid = 12037140 | doi = 10.1124/pr.54.2.233 }}</ref> [[CALCRL|CGRP receptor]]s are found throughout all the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g., [[respiratory system|respiratory]], [[endocrine system|endocrine]], [[gastrointestinal system|gastrointestinal]], [[immune system|immune]], and [[cardiovascular system|cardiovascular]]).<ref name="pmid15464043">{{cite journal | vauthors = Arulmani U, Maassenvandenbrink A, Villalón CM, Saxena PR | title = Calcitonin gene-related peptide and its role in migraine pathophysiology | journal = European Journal of Pharmacology | volume = 500 | issue = 1–3 | pages = 315–30 | date = October 2004 | pmid = 15464043 | doi = 10.1016/j.ejphar.2004.07.035 }}</ref> These [[Transmembrane receptor|transmembrane receptors]] form folded accordion-like structures embedded in the [[cell membrane]] with loops of protein on the inside (intracellular loops) and outside (extracellular loops) of the membrane. The second extracellular loop is fundamental for ligand-induced activation, with key interactions of R274/Y278/D280/W283.<ref name="pmid28572046">{{cite journal | vauthors = Woolley MJ, Simms J, Mobarec JC, Reynolds CA, Poyner DR, Conner AC | title = Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach | journal = Molecular and Cellular Endocrinology | volume = 454 | pages = 39–49 | date = October 2017 | pmid = 28572046 | doi = 10.1016/j.mce.2017.05.034 | s2cid = 13779528 | url = http://repository.essex.ac.uk/19762/1/Molecular_functions_of_ECL2_of_CGRP.pdf }}</ref>

== Regulation ==
Regulation of the CGRP gene is in part controlled by the expression of the [[mitogen-activated protein kinase]] (MAPK) [[MAPK/ERK pathway|signaling pathway]] and [[cytokine]]s like [[TNFα]] and [[iNOS]].<ref name="pmid12574409">{{cite journal | vauthors = Durham PL, Russo AF | title = Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons | journal = The Journal of Neuroscience | volume = 23 | issue = 3 | pages = 807–15 | date = February 2003 | pmid = 12574409 | pmc = 6741928 | doi = 10.1523/JNEUROSCI.23-03-00807.2003 }}</ref><ref name="pmid12684435">{{cite journal | vauthors = Schäfers M, Svensson CI, Sommer C, Sorkin LS | title = Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons | journal = The Journal of Neuroscience | volume = 23 | issue = 7 | pages = 2517–21 | date = April 2003 | pmid = 12684435 | pmc = 6742090 | doi = 10.1523/JNEUROSCI.23-07-02517.2003 }}</ref><ref name="pmid18221935">{{cite journal | vauthors = Li J, Vause CV, Durham PL | title = Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells | journal = Brain Research | volume = 1196 | pages = 22–32 | date = February 2008 | pmid = 18221935 | pmc = 2268710 | doi = 10.1016/j.brainres.2007.12.028 }}</ref> [[5-HT1 receptor|5HT1 receptor]] [[agonist]]s like [[sumatriptan]] increase intracellular calcium, which causes decreases in CGRP promoter activity.<ref name="pmid12574409" />

CGRP receptors are found in myelinated A-fiber axons which is required for ligand specificity and function of the receptor. The CGRP receptor has three subunits: receptor activity-modifying protein 1 (RAMP1), calcitonin-like receptor (CLR) and receptor component protein (RCP).<ref>{{cite journal | vauthors = Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltrán E, Vigneri S, Edvinsson L, Maassen Van Den Brink A | display-authors = 6 | title = Blocking CGRP in migraine patients - a review of pros and cons | journal = [[The Journal of Headache and Pain]] | volume = 18 | issue = 1 | pages = 96 | date = September 2017 | pmid = 28948500 | pmc = 5612904 | doi = 10.1186/s10194-017-0807-1 | doi-access = free }}</ref> The complex central receptor is the G protein-coupled receptor calcitonin receptor-like receptor (CALCRL) which is necessary for CGRP and adrenomedullin (AM receptors). For function CGRP, CALCRL must coincide with RAMP1 where the ligand-binding domain of CGRP is located. It also includes two cytoplasmic proteins that associate with the CALCRL-RAMP1 to form signal transduction. CALCRL contains the Gα subunit, which activates adenylyl cyclase and cAMP-dependent signaling pathways. Receptor-mediated transduction elevates in intracellular cAMP activate protein kinase A, which results in the phosphorylation of multiple targets, including potassium- sensitive ATP channels (KATP channels), extracellular signal-related kinases and transcription factors such as cAMP-responsive element-binding protein (CREB). In smooth muscle of neurovascular region, the elevation of cAMP upon CGRP activation results in vasodilation of the blood vessel. Chronic exposure to CGRP causes degradation of lysosomes.<ref>{{cite journal | vauthors = Edvinsson L, Haanes KA, Warfvinge K, Krause DN | title = CGRP as the target of new migraine therapies - successful translation from bench to clinic | journal = Nature Reviews. Neurology | volume = 14 | issue = 6 | pages = 338–350 | date = June 2018 | pmid = 29691490 | doi = 10.1038/s41582-018-0003-1 | s2cid = 13810025 }}</ref>

== Research ==
{{further|Calcitonin gene-related peptide receptor antagonist}}
{{primary sources|section|date=February 2018}}
{{update|section|date=February 2018}}
Increased levels of CGRP have been reported in [[migraine]] and [[temporomandibular joint disorder]] patients as well as a variety of other diseases such as cardiac failure, hypertension, and sepsis.<ref name="pmid7585923">{{cite journal | vauthors = Buzzi MG, Bonamini M, Moskowitz MA | title = Neurogenic model of migraine | journal = Cephalalgia | volume = 15 | issue = 4 | pages = 277–80 | year = 1995 | pmid = 7585923 | doi = 10.1046/j.1468-2982.1995.1504277.x | s2cid = 1403941 }}</ref><ref name="pmid1637085">{{cite journal | vauthors = Goto K, Miyauchi T, Homma S, Ohshima N | title = Calcitonin gene-related peptide in the regulation of cardiac function | journal = Annals of the New York Academy of Sciences | volume = 657 | issue = 1 | pages = 194–203 | date = June 1992 | pmid = 1637085 | doi = 10.1111/j.1749-6632.1992.tb22768.x | bibcode = 1992NYASA.657..194G | s2cid = 43409084 }}</ref><ref name="pmid2247835">{{cite journal | vauthors = Joyce CD, Fiscus RR, Wang X, Dries DJ, Morris RC, Prinz RA | title = Calcitonin gene-related peptide levels are elevated in patients with sepsis | journal = Surgery | volume = 108 | issue = 6 | pages = 1097–101 | date = December 1990 | pmid = 2247835 }}</ref><ref name="pmid7828188">{{cite journal | vauthors = Edvinsson L, Goadsby PJ | title = Neuropeptides in migraine and cluster headache | journal = Cephalalgia | volume = 14 | issue = 5 | pages = 320–7 | date = October 1994 | pmid = 7828188 | doi = 10.1046/j.1468-2982.1994.1405320.x | s2cid = 29949980 }}</ref><ref name="pmid8395342">{{cite journal | vauthors = Ferrari MD, Saxena PR | title = On serotonin and migraine: a clinical and pharmacological review | journal = Cephalalgia | volume = 13 | issue = 3 | pages = 151–65 | date = June 1993 | pmid = 8395342 | doi = 10.1046/j.1468-2982.1993.1303151.x | s2cid = 23099581 }}</ref><ref name="pmid7518321">{{cite journal | vauthors = Goadsby PJ, Edvinsson L | title = Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies | journal = Brain | volume = 117 ( Pt 3) | issue = 3 | pages = 427–34 | date = June 1994 | pmid = 7518321 | doi = 10.1093/brain/117.3.427 }}</ref><ref name="k1">{{cite web |title=What to Know About the New CGRP Migraine Treatment Options |url=https://americanmigrainefoundation.org/resource-library/what-to-know-about-the-new-anti-cgrp-migraine-treatment-options/ |access-date=23 February 2019 |website=American Migraine Foundation |vauthors=Tepper S}}</ref>

There is mounting evidence to suggest that CGRP may be beneficial in preventing the development of hypertension and cardiovascular pathologies associated with hypertension.<ref name="Calcitonin gene-related peptide: ph" /> Prophylactic therapy with calcitonin gene-related peptides (CGRPs) may have unknown fertility consequences for women of childbearing age. This is of particular concern, as females (16.6%) are more genetically predisposed to migraine than are males (7.5%).<ref>{{cite journal | vauthors = Pellesi L, Guerzoni S, Pini LA | title = Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date | journal = Clinical Pharmacology in Drug Development | volume = 6 | issue = 6 | pages = 534–547 | date = November 2017 | pmid = 28409893 | pmc = 5697612 | doi = 10.1002/cpdd.345 }}</ref>

Preclinical evidence suggests that, during a [[migraine]], activated primary sensory neurons (meningeal nociceptors) in the [[trigeminal ganglion]] release CGRP from their peripherally projecting nerve endings located within the [[meninges]].<ref name="pmid16927957">{{cite journal | vauthors = Durham PL | title = Calcitonin gene-related peptide (CGRP) and migraine | journal = Headache | volume = 46 | issue = Suppl 1 | pages = S3-8 | date = June 2006 | pmid = 16927957 | pmc = 3134175 | doi = 10.1111/j.1526-4610.2006.00483.x }}</ref><ref name="k1" /> This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, [[mast cell]] degranulation, and plasma [[extravasation]].<ref name="pmid15464043" /><ref name="pmid16927957" /><ref name="pmid1699472">{{cite journal | vauthors = Goadsby PJ, Edvinsson L, Ekman R | title = Vasoactive peptide release in the extracerebral circulation of humans during migraine headache | journal = Annals of Neurology | volume = 28 | issue = 2 | pages = 183–7 | date = August 1990 | pmid = 1699472 | doi = 10.1002/ana.410280213 | s2cid = 12568270 }}</ref><ref name="pmid16866713">{{cite journal | vauthors = Edvinsson L | title = Neuronal signal substances as biomarkers of migraine | journal = Headache | volume = 46 | issue = 7 | pages = 1088–94 | year = 2006 | pmid = 16866713 | doi = 10.1111/j.1526-4610.2006.00502.x | s2cid = 24433430 }}</ref> Human observations have further implicated the role of CGRP in the pathophysiology of migraine. Activation of primary sensory neurons in the trigeminal vascular system in humans can cause the release of CGRP. During some migraine attacks, increased concentrations of CGRP can be found in both saliva and in plasma drawn from the external jugular vein.<ref name="pmid15464043" /><ref name="pmid16927957" /><ref name="pmid1699472" /><ref name="pmid16866713" /> Furthermore, intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.<ref name="pmid11993614">{{cite journal | vauthors = Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J | title = CGRP may play a causative role in migraine | journal = Cephalalgia | volume = 22 | issue = 1 | pages = 54–61 | date = February 2002 | pmid = 11993614 | doi = 10.1046/j.1468-2982.2002.00310.x | s2cid = 24779840 | doi-access = free }}</ref><ref name="k1" />

== Medicines ==
Treatments based on [[Monoclonal antibody|monoclonal antibodies]] have been produced related to CGRP or [[Calcitonin gene-related peptide receptor antagonist|CGRP receptors]]. They have been shown to be effective in patients who experience migraine headaches, both with and without aura, and both episodic and chronic cluster headache. These are the first class of preventive medications originally designed and approved for people with migraine.<ref name="k1" /> Due to the nature of the monoclonal antibodies, they must be administered [[Route of administration#Parenteral|parenterally]], preferably by injection.<ref name="Wang2018">{{cite journal |vauthors=Wang W, Wang EQ, Balthasar JP |date=November 2008 |title=Monoclonal antibody pharmacokinetics and pharmacodynamics |journal=Clinical Pharmacology and Therapeutics |volume=84 |issue=5 |pages=548–58 |doi=10.1038/clpt.2008.170 |pmid=18784655 |s2cid=7994962}}</ref>

The first CGRP related medication approved by the FDA is called [[Erenumab]] (trade name Aimovig), produced by pharmaceutical company Amgen and Novartis. It interacts with the CGRP receptor. It is injected once monthly with a dose of 70 or 140&nbsp;mg. Few adverse effects were reported (most related to injection site reactions) and patients had a significant reduction in migraines.<ref name="k5">{{cite web | vauthors = Rosenberg J |title=FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine |url=https://www.ajmc.com/newsroom/fda-approves-erenumab-first-cgrp-inhibitor-for-prevention-of-migraine |website=AJMC.com |date=18 May 2018 | access-date = 23 February 2019 }}</ref><ref name="pmid30793254">{{cite journal | vauthors = Lattanzi S, Brigo F, Trinka E, Vernieri F, Corradetti T, Dobran M, Silvestrini M | s2cid = 67790108 | title = Erenumab for Preventive Treatment of Migraine: A Systematic Review and Meta-Analysis of Efficacy and Safety | journal = Drugs | volume = 79 | issue = 4 | pages = 417–431 | date = March 2019 | pmid = 30793254 | doi = 10.1007/s40265-019-01069-1 }}</ref>

The second approved by the FDA is called [[Fremanezumab]] (trade name Ajovy), produced by the Teva pharmaceutical company. It interacts with the CGRP protein, whose expression is related to migraine attacks. It may be administered monthly or every three months, giving options for users. Trials have shown a reduction of greater than 50% of migraine days for those who responded. There were few significant side effects during trials, most related to injection site reactions.<ref name="k3">{{cite web |title=FDA Approves Second Anti-CGRP Treatment for Migraines |url=https://americanmigrainefoundation.org/resource-library/fda-approves-second-anti-cgrp-treatment-for-migraine/ |website=American Migraine Foundation | access-date = 23 February 2019 }}</ref><ref name="pmid30311143">{{cite journal | vauthors = Bigal ME, Rapoport AM, Silberstein SD, Walter S, Hargreaves RJ, Aycardi E | s2cid = 52962394 | title = From LBR-101 to Fremanezumab for Migraine | journal = CNS Drugs | volume = 32 | issue = 11 | pages = 1025–1037 | date = November 2018 | pmid = 30311143 | doi = 10.1007/s40263-018-0579-4 }}</ref>

The third approved by the FDA is called [[Galcanezumab]] (trade name Emgality), produced by the Eli Lilly Company. It interacts with the CGRP protein, whose expression is related to migraine attacks. It is injected once a month, after the first month having a double dose. The main side effects are injection site reactions.<ref name="k4">{{cite web |title=Lilly's Emgality™ (galcanezumab-gnlm) Receives U.S. FDA Approval for the Preventive Treatment of Migraine in Adults |url=https://investor.lilly.com/news-releases/news-release-details/lillys-emgalitytm-galcanezumab-gnlm-receives-us-fda-approval |website=Lilly | access-date = 23 February 2019 }}</ref><ref name="pmid30378008">{{cite journal | vauthors = Lamb YN | s2cid = 53107438 | title = Galcanezumab: First Global Approval | journal = Drugs | volume = 78 | issue = 16 | pages = 1769–1775 | date = November 2018 | pmid = 30378008 | doi = 10.1007/s40265-018-1002-7 }}</ref>

Approved by the FDA in February 2020, [[ubrogepant]] (Ubrelvy) is an oral medication manufactured by AbbVie.

Also FDA approved in February 2020, [[Eptinezumab]] (Vyapti), is an intravenous migraine prophylactic medication manufactured by Lundbeck.

In September 2021 the FDA approved [[Qulipta]] (atogepant), the first oral CGRP receptor antagonist approved to prevent chronic migraine.<ref name="q1">{{cite web |title=FDA Approves Qulipta (atogepant) Oral CGRP Receptor Antagonist for the Preventive Treatment of Migraine |url=https://www.drugs.com/newdrugs/fda-approves-qulipta-atogepant-oral-cgrp-receptor-antagonist-preventive-migraine-5674.html |website=Drugs.com | access-date = 19 September 2024 }}</ref>

The [[Cannabinoid|phytocannabinoids]] delta-9 [[tetrahydrocannabinol]] (Δ9-THC) and its [[Redox|oxidative]] byproduct [[cannabinol]] (CBN) are found to induce a [[Cannabinoid receptor type 1|CB1]] and [[Cannabinoid receptor type 2|CB2]] [[cannabinoid receptor]]-independent release of calcitonin gene-related peptide from [[capsaicin]]-sensitive [[Mural cell|perivascular]] [[sensory nerve]]s, an action that other psychotropic cannabinoids cannot do.<ref>{{Cite web |title=Degradants Formed During Phytocannabinoid Processing |url=https://www.caymanchem.com/news/degradants-formed-during-phytocannabinoid-processing |access-date=2023-05-10 |website=www.caymanchem.com |language=en}}</ref><ref name="pmid12040079">{{cite journal | vauthors = Zygmunt PM, Andersson DA, Hogestatt ED | title = Δ9-Tetrahydrocannabinol and Cannabinol Activate Capsaicin-Sensitive Sensory Nerves via a CB1 and CB2 Cannabinoid Receptor-Independent Mechanism | journal = The Journal of Neuroscience | volume = 22 | issue = 11 | pages = 4720–7 | date = June 2002 | pmid = 12040079 | pmc = 6758782 | doi = 10.1523/JNEUROSCI.22-11-04720.2002}}</ref>

== References ==
{{Reflist|colwidth = 30em}}

== External links ==
* {{MeshName|Calcitonin+Gene-Related+Peptide}}

{{Neuropeptides}}
{{Sigma receptor modulators}}

[[Category:Neuropeptides]]