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. 2009 Mar 28;10(3):137–143. doi: 10.1007/s10194-009-0112-8

Calcitonin gene-related peptide in blood: is it increased in the external jugular vein during migraine and cluster headache? A review

Peer Tfelt-Hansen 1,✉, Han Le 1
PMCID: PMC3451987  PMID: 19330286

Abstract

The involvement of calcitonin gene-related peptide (CGRP) in migraine pathophysiological mechanisms is shown by the facts that CGRP can induce migraine and that two CGRP antagonists, olcegepant and telcagepant, are effective in the treatment of migraine attacks. Increase of the neuropeptide CGRP during migraine and cluster headache attacks in the extracerebral circulation as measured in the external jugular vein (EJV) has been regarded as an established fact. Then in 2005, a study, using the migraine patients as their own controls, showed; however, no changes of CGRP in EJV. For migraine there is thus some uncertainty as to whether CGRP is increased in all migraine patients and more research is needed. In contrast, there are three ‘positive’ studies in cluster headache in which both sumatriptan, O2 and spontaneous resolution normalized CGRP. The source of an increase of CGRP in EJV is most likely a ‘nervous vasodilatory drive’ in the extracranial vascular bed. It remains an enigma how the observed increase of CGRP in the EJV fits into the mechanisms of migraine and cluster headache.

Keywords: Migraine, Cluster headache, Calcitonin gene-related peptide, Extracranial circulation

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References

  • 1.Lassen LH, Tfelt-Hansen P, Jacobsen VB, Haderslev PA, Sperling B, Iversen HK, Olesen J. The effect of intravenous infusion of human calcitonin gene-related peptide on middle cerebral artery and cerebral blood flow in migraine patients. J Headache Pain. 2008;9:151–157. doi: 10.1007/s10194-008-0036-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier et al (2004) BIBN 4096 BS Clinical Proof of Concept Study Group Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Eng J Med 350:1104–1110 [DOI] [PubMed]
  • 3.Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, et al. Randomized controlled trial of an horal CGRP antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70:1304–1312. doi: 10.1212/01.WNL.0000286940.29755.61. [DOI] [PubMed] [Google Scholar]
  • 4.Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet. 2008;372:2115–2125. doi: 10.1016/S0140-6736(08)61626-8. [DOI] [PubMed] [Google Scholar]
  • 5.Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298:240–242. doi: 10.1038/298240a0. [DOI] [PubMed] [Google Scholar]
  • 6.Brain SD, Cambridge H. Calcitonin gene-related peptide: vasoactive effects and potential therapeutic role. Gen Pharmacol. 1996;1996(27):607–611. doi: 10.1016/0306-3623(95)00125-5. [DOI] [PubMed] [Google Scholar]
  • 7.Sexton PM. Central nervous binding sites for calcitonin and calcitonin gene-related peptide. Mol Neurobiol. 1991;5:251–273. doi: 10.1007/BF02935550. [DOI] [PubMed] [Google Scholar]
  • 8.Edvinsson L, Goadsby PJ. Neuropeptides in the cerebral circulation: relevance to migraine. Cephalalgia. 1995;15:272–276. doi: 10.1046/j.1468-2982.1995.1504272.x. [DOI] [PubMed] [Google Scholar]
  • 9.Edvinsson L. Functional role of perivascular peptides in the control of the cerebral circulation. Trends Neurosci. 1985;9:126–131. doi: 10.1016/0166-2236(85)90050-5. [DOI] [Google Scholar]
  • 10.Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett. 1985;62:131–136. doi: 10.1016/0304-3940(85)90296-4. [DOI] [PubMed] [Google Scholar]
  • 11.Ponyer DR. Calcitonin gene-related peptide: multiple actions, multiple receptors. Pharmacol Ther. 1992;56:23–51. doi: 10.1016/0163-7258(92)90036-Y. [DOI] [PubMed] [Google Scholar]
  • 12.Hill RG, Oliver KR (2007) Neuropeptide and kinin antagonists. Handb Exp Pharmacol 177:181–216 [DOI] [PubMed]
  • 13.van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev. 1997;21:649–678. doi: 10.1016/S0149-7634(96)00023-1. [DOI] [PubMed] [Google Scholar]
  • 14.Powell KJ, Ma W, Sutak M, Doods H, Quirion R, Jhamandas K. Blockade and reversal of spinal morphine tolerance by peptide and non-peptide calcitonin gene-related peptide receptor antagonists. Br J Pharmacol. 2000;131:875–884. doi: 10.1038/sj.bjp.0703655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Wimalawansa SJ. Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev. 1996;17:533–585. doi: 10.1210/edrv-17-5-533. [DOI] [PubMed] [Google Scholar]
  • 16.Arulmani U, MaasenVanDenBrink A, Villalon CM, Saxena PR. Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol. 2004;500:315–330. doi: 10.1016/j.ejphar.2004.07.035. [DOI] [PubMed] [Google Scholar]
  • 17.Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine attacks. Ann Neurol. 1990;28:183–187. doi: 10.1002/ana.410280213. [DOI] [PubMed] [Google Scholar]
  • 18.Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33:48–56. doi: 10.1002/ana.410330109. [DOI] [PubMed] [Google Scholar]
  • 19.Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attack therapies. Brain. 1994;117:427–434. doi: 10.1093/brain/117.3.427. [DOI] [PubMed] [Google Scholar]
  • 20.Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitro-glycerin-induced cluster headache attack. Pain. 1995;60:119–123. doi: 10.1016/0304-3959(94)00097-X. [DOI] [PubMed] [Google Scholar]
  • 21.Fanciullacci M, Alessandri M, Sicuteri R, Marabini S. Responsiveness of the trigeminovascular system to nitroglycerin in cluster headache patients. Brain. 1997;120:283–288. doi: 10.1093/brain/120.2.283. [DOI] [PubMed] [Google Scholar]
  • 22.Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J. No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol. 2005;58:561–563. doi: 10.1002/ana.20605. [DOI] [PubMed] [Google Scholar]
  • 23.Schifter S. Circulating concentrations of calcitonin gene-related peptide (CGRP) in normal man determined with a new, highly sensitive radioimmunoassay. Peptides. 1991;12:365–369. doi: 10.1016/0196-9781(91)90027-M. [DOI] [PubMed] [Google Scholar]
  • 24.Goadsby PJ. Calcitonin gene-related peptide (CGRP) antagonists and migraine: is it a new area? Neurology. 2008;70:1300–1301. doi: 10.1212/01.wnl.0000309214.25038.fd. [DOI] [PubMed] [Google Scholar]
  • 25.Colonna DM, Meng W, Deal DD, Busija DW. Calcitonin gene-related peptide promotes cerebrovascular dilation during cortical spreading depression in rabbits. Am J Physiol. 1994;266:H1095–H1102. doi: 10.1152/ajpheart.1994.266.3.H1095. [DOI] [PubMed] [Google Scholar]
  • 26.Wahl M, Schilling L, Parsons AA, Kaumam A. Involvement of calcitonin gene-related peptide and nitric oxide (NO) in pial artery dilatation elicited by cortical spreading depression. Brain Res. 1994;637:204–210. doi: 10.1016/0006-8993(94)91234-3. [DOI] [PubMed] [Google Scholar]
  • 27.Piper RD, Edvinsson L, Ekman R, Lambert GA. Cortical spreading depression does not result in the release of calcitonin gene-related peptide into the external jugular vein of the cat: relevance to human migraine. Cephalalgia. 1993;13:180–183. doi: 10.1046/j.1468-2982.1993.1303180.x. [DOI] [PubMed] [Google Scholar]
  • 28.Davis DD, Story HE. Carotid circulation in the domestic cat. Publications of Field Museum of Nathional History. 1943;28:5–47. [Google Scholar]
  • 29.Edvinsson L, Nilsson E, Jansen-Olesen I. Inhibitory effect of BIBN4096BS, CGRP(8–37), a CGRP antibody and an RNA-Spigelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery. Br J Pharmacol. 2007;150:633–640. doi: 10.1038/sj.bjp.0707134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Edvinsson L, Tfelt-Hansen P. The blood–brain barrier in migraine treatment. Cephalalgia. 2008;28:1245–1258. doi: 10.1111/j.1468-2982.2008.01675.x. [DOI] [PubMed] [Google Scholar]
  • 31.Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol. 1988;23:193–196. doi: 10.1002/ana.410230214. [DOI] [PubMed] [Google Scholar]
  • 32.Goadsby PJ, Duckworth JW. Effect of stimulation of trigeminal ganglion on cerebral blood flow in cats. Am J Physiol. 1987;253:R270–R274. doi: 10.1152/ajpregu.1987.253.2.R270. [DOI] [PubMed] [Google Scholar]
  • 33.Goadsby PJ, Lambert GA, Lance JW. Stimulation of trgigeminal ganglion increases flow in the extracerebral but not the cerebral circulation of the monkey. Brain Res. 1986;381:63–67. doi: 10.1016/0006-8993(86)90690-6. [DOI] [PubMed] [Google Scholar]
  • 34.Escott KJ, Beattie DT, Connor HE, Brain SD. Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res. 1995;669:93–99. doi: 10.1016/0006-8993(94)01247-F. [DOI] [PubMed] [Google Scholar]
  • 35.Limmroth V, Katsarava Z, Liendent B, Schmitz K, Diener HC, Michel MC. An in vivo rat model to study calcitonin gene related peptide release following activation of the trigeminal vascular system. Pain. 2001;92:101–106. doi: 10.1016/S0304-3959(00)00475-9. [DOI] [PubMed] [Google Scholar]
  • 36.Zagami AS, Goadsby PJ, Edvinsson L. Stimulation of the superior sagital sinus in the rat causes release of vasoactive peptides. Neuropeptides. 1990;16:69–75. doi: 10.1016/0143-4179(90)90114-E. [DOI] [PubMed] [Google Scholar]
  • 37.Knight E, Edvinsson L, Goadsby PJ. 4991W93 inhibits release of calcitonin gene-related peptide in the cat but only in doses with 5HT(1B/1D) receptor agonist activity. Neuropharmacology. 2001;40:520–525. doi: 10.1016/S0028-3908(00)00187-8. [DOI] [PubMed] [Google Scholar]
  • 38.Offenhauser N, Zinck T, Hoffmann J, Schiemann K, Schuh-Hofer S, Rohde W, Arnold G, Dirnagl U, Jansen-Olesen I, Reuter U. CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalagia. 2005;25:225–236. doi: 10.1111/j.1468-2982.2004.00845.x. [DOI] [PubMed] [Google Scholar]
  • 39.Headache Classification Committee of the International Headache Society (2004) Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain. Cephalalgia 24 (suppl 1):9–160 [PubMed]
  • 40.Durham PL, Russo AF. Regulation of calcitonin gene-related peptide secretion by serotonergic antimigraine drugs. J Neurosci. 1999;19:3423–3429. doi: 10.1523/JNEUROSCI.19-09-03423.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Hansen JM, Petersen J, Wienecke T, Olsen KS, Jensen LT, Ashina M (2008) Sumatriptan does no change calcitonin gene-related peptide in the cephalic and extracephalic circulation in healthy volunteers. Abstract book. European Headache and Migraine nTrust International Congress, p 46 [DOI] [PMC free article] [PubMed]
  • 42.Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RS, et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain. 2005;128:932–939. doi: 10.1093/brain/awh416. [DOI] [PubMed] [Google Scholar]
  • 43.Thomsen L, Kruuse C, Iversen H, Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol. 1994;1:73–80. doi: 10.1111/j.1468-1331.1994.tb00053.x. [DOI] [PubMed] [Google Scholar]
  • 44.Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Trequattrini A, Palumbo R. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both ictally and interictally. Cephalalgia. 1995;15:384–390. doi: 10.1046/j.1468-2982.1995.1505384.x. [DOI] [PubMed] [Google Scholar]
  • 45.Ghatei MA, Stratton MR, Allen JM, Joplin GF, Polak JM, Bloom SR. Co-secretion of calcitonin gene-related peptide, gastrin-releasing peptide and ACTH by a carcinoid tumour metastasazing to the cerebellum. Postgrad Med J. 1987;63:123–130. doi: 10.1136/pgmj.63.736.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Schon F, Thomas DT, Jewkes DA, Ghatei M, Mulderry PK, Bloom SR. Failure to detect plasma neuropeptide release during trigeminal thermocoagulation. J Neurol Neurosurg Psychiatr. 1987;50:642–643. doi: 10.1136/jnnp.50.5.642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Juhasz G, Zsombok T, Modos EA, Olajos S, Jakab B, Nemeth J, et al. No-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain. 2003;106:461–470. doi: 10.1016/j.pain.2003.09.008. [DOI] [PubMed] [Google Scholar]
  • 48.Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolesanyri J, Bagdy G. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced attack. Cephalalalgia. 2005;25:179–183. doi: 10.1111/j.1468-2982.2005.00836.x. [DOI] [PubMed] [Google Scholar]
  • 49.Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J. Calcitonin gene-related peptide during nitric-oxide headache in patients with chronic tension-type headache. Eur J Neurol. 2001;8:173–178. doi: 10.1046/j.1468-1331.2001.00191.x. [DOI] [PubMed] [Google Scholar]
  • 50.Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V. Nitric oxide, prostaglandin and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia. 2000;20:903–918. doi: 10.1046/j.1468-2982.2000.00146.x. [DOI] [PubMed] [Google Scholar]
  • 51.Friberg L, Olesen J, Olsen TS, Karle A, Ekman R, Fahrenkrug J. Absence of vasoactive peptide release from brain to cerebral circulation during onset of migraine with aura. Cephalalgia. 1994;14:47–54. doi: 10.1046/j.1468-2982.1994.1401047.x. [DOI] [PubMed] [Google Scholar]
  • 52.Frese A, Schilgen M, Edvinsson L, Frandsen E, Evers S. Calcitonin gene-related peptide in cervicogenic headache. Cephalalgia. 2005;25:700–703. doi: 10.1111/j.1468-2982.2004.00940.x. [DOI] [PubMed] [Google Scholar]
  • 53.Spanner R ed (1970) Spalteholz-Spanner Handatlas der Anatomie des Menchen, 16th edn. Second Part. Scheltema, Holkema, Amsterdam
  • 54.Shenkin HA, Harmel MN, Kety SS. Dynamic anatomy of the cerebral circulation. Arch Neurol Psychiatry. 1948;60:240–252. doi: 10.1001/archneurpsyc.1948.02310030021002. [DOI] [PubMed] [Google Scholar]
  • 55.Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanism of migraine aura revealed by functional MRI in the visual cortex. Proc Natl Acad Sci USA. 2001;98:4687–4692. doi: 10.1073/pnas.071582498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Olesen J, Friberg L, Olsen TS, Iversen HK, Lassen NA, Andersen AR, Karle A. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol. 1990;28:791–798. doi: 10.1002/ana.410280610. [DOI] [PubMed] [Google Scholar]
  • 57.Iversen HK, Nielsen TH, Olesen J, Tfelt-Hansen P. Arterial responses during migraine headaches. Lancet. 1990;336:837–839. doi: 10.1016/0140-6736(90)92339-J. [DOI] [PubMed] [Google Scholar]
  • 58.Nielsen TH, Tfelt-Hansen P, Iversen HK. Asymmetry of temporal arterial diameter during spontaneous attacks of cluster headache. Headache. 2009;49:383–385. doi: 10.1111/j.1526-4610.2008.01280.x. [DOI] [PubMed] [Google Scholar]
  • 59.Drummond PD, Gonski A, Lance JW. Facial flushing after thermocoagulation of the Gasserian ganglion. J Neurol Neurosurg Psychiatr. 1983;46:611–616. doi: 10.1136/jnnp.46.7.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Drummond PD, Lance JW. Thermographic changes in cluster headache. Neurology. 1984;34:1292–1298. doi: 10.1212/wnl.34.10.1292. [DOI] [PubMed] [Google Scholar]
  • 61.Drummond PD, Lance JW. Facial temperature in migraine, tension-vascular and tension headache. Cephalalgia. 1984;4:149–158. doi: 10.1046/j.1468-2982.1984.0403149.x. [DOI] [PubMed] [Google Scholar]
  • 62.Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J. BIBN4096BS antagonizes human α-calcitonin gene related peptide-induced headache and extracerebral artery dilatation. Clin Pharmacol Ther. 2005;77:202–213. doi: 10.1016/j.clpt.2004.10.001. [DOI] [PubMed] [Google Scholar]

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