CGRP in Human Models of Migraine

  • Håkan AshinaEmail author
  • Henrik Winther Schytz
  • Messoud Ashina
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 255)


Over the past three decades, calcitonin gene-related peptide (CGRP) has emerged as a key molecule. Provocation experiments have demonstrated that intravenous CGRP infusion induces migraine-like attacks in migraine with and without aura patients. In addition, these studies have revealed a heterogeneous CGRP response, i.e., some migraine patients develop migraine-like attacks after CGRP infusion, while others do not. The role of CGRP in human migraine models has pointed to three potential sites of CGRP-induced migraine: (1) vasodilation via cyclic adenosine monophosphate (cAMP) and possibly cyclic guanosine monophosphate (cGMP); (2) activation of trigeminal sensory afferents, and (3) modulation of deep brain structures. In the future, refined human experimental studies will continue to unveil the role of CGRP in migraine pathogenesis.


CGRP Human provocation models Migraine 


  1. Akerman S, Holland PR, Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12(10):570–584PubMedCrossRefGoogle Scholar
  2. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298(5871):240–244PubMedPubMedCentralCrossRefGoogle Scholar
  3. Asghar MS, Hansen AE, Kapijimpanga T, van der Geest RJ, van der Koning P, Larsson HB, Olesen J, Ashina M (2010) Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology 75(17):1520–1526PubMedCrossRefGoogle Scholar
  4. Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Koning PV, Larsson HB, Olesen J, Ashina M (2011) Evidence for a vascular factor in migraine. Ann Neurol 69(4):635–645PubMedCrossRefGoogle Scholar
  5. Asghar MS, Hansen AE, Larsson HB, Olesen J, Ashina M (2012) Effect of CGRP and sumatriptan on the BOLD response in visual cortex. J Headache Pain 13(2):159–166PubMedPubMedCentralCrossRefGoogle Scholar
  6. Asghar MS, Becerra L, Larsson HB, Borsook D, Ashina M (2016) Calcitonin gene-related peptide modulates heat nociception in the human brain – an fMRI study in healthy volunteers. PLoS One 11(3):e0150334PubMedPubMedCentralCrossRefGoogle Scholar
  7. Ashina M, Hansen JM, Olesen J (2013) Pearls and pitfalls in human pharmacological models of migraine: 30 years’ experience. Cephalalgia 33(8):540–553PubMedCrossRefGoogle Scholar
  8. Ashina M, Hansen JM, Á Dunga BO, Olesen J (2017) Human models of migraine – short-term pain for long-term gain. Nat Rev Neurol 13(12):713–724PubMedCrossRefGoogle Scholar
  9. Charles AC, Baca SM (2013) Cortical spreading depression and migraine. Nat Rev Neurol 9(11):637–644PubMedCrossRefGoogle Scholar
  10. Christiansen I, Thomsen LL, Daugaard D, Ulrich V, Olesen J (1999) Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia 19(7):660–667PubMedCrossRefGoogle Scholar
  11. de Hoon JN, Pickkers P, Smits P, Struijker-Boudier HA, Van Bortel LM (2003) Calcitonin gene-related peptide: exploring its vasodilating mechanism of action in humans. Clin Pharmacol Ther 73(4):312–321PubMedCrossRefGoogle Scholar
  12. Edvinsson L, Fredholm BB, Hamel E, Jansen I, Verrecchia C (1985) Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation or release of an endothelium-derived relaxing factor in the cat. Neurosci Lett 58(2):213–217PubMedPubMedCentralCrossRefGoogle Scholar
  13. Edvinsson L, Ekman R, Jansen I, McCulloch J, Uddman R (1987) Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J Cereb Blood Flow Metab 7(6):720–728PubMedCrossRefGoogle Scholar
  14. Eftekhari S, Edvinsson L (2011) Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci 12:112PubMedPubMedCentralCrossRefGoogle Scholar
  15. Eftekhari S, Gaspar RC, Roberts R, Chen TB, Zeng Z, Villarreal S, Edvinsson L, Salvatore CA (2016) Localization of CGRP receptor components and receptor binding sites in rhesus monkey brainstem: a detailed study using in situ hybridization, immunofluorescence, and autoradiography. J Comp Neurol 524(1):90–118PubMedCrossRefGoogle Scholar
  16. Friberg L, Olesen J, Olsen TS, Karle A, Ekman R, Fahrenkrug J (1994) Absence of vasoactive peptide release from brain to cerebral circulation during onset of migraine with aura. Cephalalgia 14(1):47–54PubMedCrossRefGoogle Scholar
  17. Giniatullin R, Nistri A, Fabbretti E (2008) Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol Neurobiol 37(1):83–90PubMedCrossRefGoogle Scholar
  18. Goadsby PJ, Edvinsson L, Ekman R (1988) Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 23(2):193–196PubMedPubMedCentralCrossRefGoogle Scholar
  19. Guo S, Olesen J, Ashina M (2014) Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain 137(Pt 11):2951–2959PubMedCrossRefGoogle Scholar
  20. Guo S, Vollesen AL, Olesen J, Ashina M (2016) Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain 157(12):2773–2781PubMedCrossRefGoogle Scholar
  21. Hansen JM, Ashina M (2014) Calcitonin gene-related peptide and migraine with aura: a systematic review. Cephalalgia 34(9):695–707PubMedCrossRefGoogle Scholar
  22. Hansen JM, Thomsen LL, Olesen J, Ashina M (2008) Calcitonin gene-related peptide does not cause the familial hemiplegic migraine phenotype. Neurology 71(11):841–847PubMedCrossRefGoogle Scholar
  23. Hansen JM, Hauge AW, Olesen J, Ashina M (2010) Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30(10):1179–1186PubMedCrossRefGoogle Scholar
  24. Hansen JM, Thomsen LL, Olesen J, Ashina M (2011) Calcitonin gene-related peptide does not cause migraine attacks in patients with familial hemiplegic migraine. Headache 51(4):544–553PubMedCrossRefGoogle Scholar
  25. Headache Classification Committee of the International Headache Society (1988) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):1–96Google Scholar
  26. Hostetler ED, Joshi AD, Sanabria-Bohórquez S, Fan H, Zeng Z, Purcell M, Gantert L, Riffel K, Williams M, O’Malley S, Miller P, Selnick HG, Gallicchio SN, Bell IM, Salvatore CA, Kane SA, Li CC, Hargreaves RJ, de Groot T, Bormans G, Van Hecken A, Derdelinckx I, de Hoon J, Reynders T, Declercq R, De Lepeleire I, Kennedy WP, Blanchard R, Marcantonio EE, Sur C, Cook JJ, Van Laere K, Evelhoch JL (2013) In vivo quantification of calcitonin gene-related peptide (CGRP) receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography (PET) tracer [11C]MK-4232. J Pharmacol Exp Ther 347(2):478–486PubMedCrossRefGoogle Scholar
  27. Iversen HK, Olesen J, Tfelt-Hansen P (1989) Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 38(1):17–24PubMedCrossRefGoogle Scholar
  28. Jansen-Olesen I, Mortensen A, Edvinsson L (1996) Calcitonin gene-related peptide is released from capsaicin-sensitive nerve fibres and induces vasodilatation of human cerebral arteries concomitant with activation of adenylyl cyclase. Cephalalgia 16(5):310–316PubMedCrossRefGoogle Scholar
  29. Khan S, Deen M, Hougaard A, Amin FM, Ashina M (2017a) Reproducibility of migraine-like attacks induced by phosphodiesterase-3-inhibitor cilostazol. Cephalalgia. PubMedCrossRefGoogle Scholar
  30. Khan S, Olesen A, Ashina M (2017b) CGRP, a target for preventive therapy in migraine and cluster headache: systematic review of clinical data. Cephalalgia. PubMedCrossRefGoogle Scholar
  31. Kruuse C, Thomsen LL, Birk S, Olesen J (2003) Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 126(Pt 1):241–247PubMedCrossRefGoogle Scholar
  32. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalgia 22(1):54–61PubMedPubMedCentralCrossRefGoogle Scholar
  33. Lassen LH, Jacobsen VB, Haderslev PA, Sperling B, Iversen HK, Olesen J, Tfelt-Hansen P (2008) Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients. J Headache Pain 9(3):151–157PubMedPubMedCentralCrossRefGoogle Scholar
  34. Lennerz JK, Rühle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF, Messlinger K (2008) Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol 507(3):1277–1299PubMedCrossRefGoogle Scholar
  35. Levy D, Burstein R, Strassman AM (2005) Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 58(5):698–705PubMedCrossRefGoogle Scholar
  36. McCulloch J, Uddman R, Kingman TA, Edvinsson L (1986) Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A 83(15):5731–5735PubMedPubMedCentralCrossRefGoogle Scholar
  37. Melo-Carrillo A, Noseda R, Nir RR, Schain AJ, Stratton J, Strassman AM, Burstein R (2017a) Selective inhibition of trigeminovascular neurons by fremanezumab: a humanized monoclonal anti-CGRP antibody. J Neurosci 37(30):7149–7163PubMedPubMedCentralCrossRefGoogle Scholar
  38. Melo-Carrillo A, Strassman AM, Nir RR, Schain AJ, Noseda R, Stratton J, Burstein R (2017b) Fremanezumab – a humanized monoclonal anti-CGRP antibody – inhibits thinly myelinated (Aδ) but not unmyelinated (C) meningeal nociceptors. J Neurosci 37(44):10587–10596PubMedPubMedCentralCrossRefGoogle Scholar
  39. Olesen J, Tfelt-Hansen P, Ashina M (2009) Finding new drug targets for the treatment of migraine attacks. Cephalalgia 29(9):909–920PubMedCrossRefGoogle Scholar
  40. Pedersen-Bjergaard U, Nielsen LB, Jensen K, Edvinsson L, Jansen I, Olesen J (1991) Calcitonin gene-related peptide, neurokinin A and substance P: effects on nociception and neurogenic inflammation in human skin and temporal muscle. Peptides 12(2):333–337PubMedPubMedCentralCrossRefGoogle Scholar
  41. Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J (2005) BIBN4096BS antagonizes human alpha-calcitonin gene related peptide-induced headache and extracerebral artery. Clin Pharmacol Ther 77(3):202–213PubMedCrossRefGoogle Scholar
  42. Piper RD, Edvinsson L, Ekman R, Lambert GA (1993) 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 13(3):180–183PubMedCrossRefGoogle Scholar
  43. Pozo-Rosich P, Storer RJ, Charbit AR, Goadsby PJ (2015) Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. Cephalalgia 35(14):1298–1307PubMedCrossRefGoogle Scholar
  44. Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM (1983) Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature 304(5922):129–135PubMedPubMedCentralCrossRefGoogle Scholar
  45. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M (2009) PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 132(Pt 1):16–25PubMedCrossRefGoogle Scholar
  46. Schytz HW, Hargreaves R, Ashina M (2017) Challenges in developing drugs for primary headaches. Prog Neurobiol 152:70–88PubMedCrossRefGoogle Scholar
  47. Thomsen LL, Kruuse C, Iversen HK, Olesen J (1994) A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1(1):73–80PubMedCrossRefGoogle Scholar
  48. Tozzi A, de Iure A, Di Filippo M, Costa C, Caproni S, Pisani A, Bonsi P, Picconi B, Cupini LM, Materazzi S, Geppetti P, Sarchielli P, Calabresi P (2012) Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc Natl Acad Sci U S A 109(46):18985–18990PubMedPubMedCentralCrossRefGoogle Scholar
  49. Tvedskov JF, Tfelt-Hansen P, Petersen KA, Jensen LT, Olesen J (2010) CGRP receptor antagonist olcegepant (BIBN4096BS) does not prevent glyceryl trinitrate-induced migraine. Cephalalgia 30(11):1346–1353PubMedCrossRefGoogle Scholar
  50. Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J (1985) Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 62(1):131–136PubMedPubMedCentralCrossRefGoogle Scholar
  51. Uddman R, Tajti J, Hou M, Sundler F, Edvinsson L (2002) Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. Cephalalgia 22(2):112–116PubMedCrossRefGoogle Scholar
  52. van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21(5):649–678PubMedCrossRefGoogle Scholar
  53. Yu Y, Lundeberg T, Yu LC (2002) Role of calcitonin gene-related peptide and its antagonist on the evoked discharge frequency of wide dynamic range neurons in the dorsal horn of the spinal cord in rats. Regul Pept 103(1):23–27PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Håkan Ashina
    • 1
    Email author
  • Henrik Winther Schytz
    • 1
  • Messoud Ashina
    • 1
  1. 1.Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

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