, Volume 7, Issue 2, pp 164–175 | Cite as

CGRP receptor antagonism and migraine

Review Article


Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. αCGRP is prominently localized in primary spinal afferent C and AA fibers of sensory ganglia, and βCGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.

Key Words

Migraine CGRP trigeminovascular CGRP receptor antagonists 


  1. 1.
    Ray B, Wolff H. Experimental studies on headache: pain sensitive structures of the head and their significance in headache. Arc Surg 1940;4: 813–856.Google Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    Tajti J, Uddman R, Möller S, Sundler F, Edvinsson L. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst 1999;76: 176–183.PubMedCrossRefGoogle Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    Goadsby PJ. Inhibition of calcitonin gene-related peptide by h-CGRP8–37 antagonizes the cerebral dilator response from nasociliary nerve stimulation in the cat. Neurosci Lett 1993;151: 13–16.PubMedCrossRefGoogle Scholar
  6. 6.
    Edvinsson L, Mulder H, Goadsby PJ, Uddman R. Calcitonin gene-related peptide and nitric oxide in the trigeminal ganglion: cerebral vasodilatation from trigeminal nerve stimulation involves mainly calcitonin gene-related peptide. J Auton Nerv Syst 1998;70: 15–22.PubMedCrossRefGoogle Scholar
  7. 7.
    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: 240–244.PubMedCrossRefGoogle Scholar
  8. 8.
    Mulderry PK, Ghatei MA, Spokes RA, et al. Differential expression of α-CGRP and β-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience 1988;25: 195–205.PubMedCrossRefGoogle Scholar
  9. 9.
    Brain SD, Cambridge H. Calcitonin gene-related peptide: vasoactive effects and potential therapeutic role. Gen Pharmacol 1996;27: 607–611.PubMedGoogle Scholar
  10. 10.
    Sexton PM. Central nervous system binding sites for calcitonin and calcitonin gene-related peptide. Mol Neurobiol 1991;5: 251–273.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Gendek-Kubiak H, Kmieć BL. Immunolocalization of CGRP, NPY and PGP 9.5 in guinea pig skin. Folia Morphol (Warsz) 2004;63: 115–117.Google Scholar
  13. 13.
    Swartling C, Naver H, Pihl-Lundin I, Hagforsen E, Vahlquist A. Sweat gland morphology and periglandular innervation in essential palmar hyperhidrosis before and after treatment with intradermal botulinum toxin. J Am Acad Dermatol 2004;51: 739–745.PubMedCrossRefGoogle Scholar
  14. 14.
    Fernandez HL, Ross GS, Nadelhaft I. Neurogenic calcitonin gene-related peptide: a neurotrophic factor in the maintenance of acetylcholinesterase molecular forms in adult skeletal muscles. Brain Res 1999;844: 83–97.PubMedCrossRefGoogle Scholar
  15. 15.
    Hayakawa T, Kuwahara S, Maeda S, Tanaka K, Seki M. Distribution of vagal CGRP-immunoreactive fibers in the lower esophagus and the cardia of the stomach of the rat. J Chem Neuroanat 2009;38: 124–129.PubMedCrossRefGoogle Scholar
  16. 16.
    Hökfelt T, Arvidsson U, Ceccatelli S, et al. Calcitonin generelated peptide in the brain, spinal cord, and some peripheral systems. Ann N Y Acad Sci 1992;657: 119–134.PubMedCrossRefGoogle Scholar
  17. 17.
    Liu Y, Zhang M, Broman J, Edvinsson L. Central projections of sensory innervation of the rat superficial temporal artery. Brain Res 2003;966: 126–133.PubMedCrossRefGoogle Scholar
  18. 18.
    Arbab MA, Delgado T, Wiklund L, Svendgaard NA. Brain stem terminations of the trigeminal and upper spinal ganglia innervation of the cerebrovascular system: WGA-HRP transganglionic study. J Cereb Blood Flow Metab 1988;8: 54–63.PubMedGoogle Scholar
  19. 19.
    Poyner DR. Calcitonin gene-related peptide: multiple actions, multiple receptors. Pharmacol Ther 1992;56: 23–51.PubMedCrossRefGoogle Scholar
  20. 20.
    Gulbenkian S, Uddman R, Edvinsson L. Neuronal messengers in the human cerebral circulation. Peptides 2001;22: 995–1007.PubMedCrossRefGoogle Scholar
  21. 21.
    Gregg KV, Bishop GA, King JS. Fine structural analysis of calcitonin gene-related peptide in the mouse inferior olivary complex. J Neurocytol 1999;28: 431–438.PubMedCrossRefGoogle Scholar
  22. 22.
    Quayle JM, Bonev AD, Brayden JE, Nelson MT. Calcitonin gene-related peptide activated ATP-sensitive K+ currents in rabbit arterial smooth muscle via protein kinase A. J Physiol 1994;475: 9–13.PubMedGoogle Scholar
  23. 23.
    Edvinsson L. Functional role of perivascular peptides in the control of cerebral circulation. Trends Neurosci 1985;8: 126–131.CrossRefGoogle Scholar
  24. 24.
    Rossi SG, Dickerson IM, Rotundo RL. Localization of the calcitonin gene-related peptide receptor complex at the vertebrate neuromuscular junction and its role in regulating acetylcholinesterase expression. J Biol Chem 2003;278: 24994–25000.PubMedCrossRefGoogle Scholar
  25. 25.
    Todd KJ, Robitaille R. Neuron-glia interactions at the neuromuscular synapse. Novartis Found Symp 2006;276: 222–229; discussion 229–237, 275–281.PubMedCrossRefGoogle Scholar
  26. 26.
    Al-Kazwini SJ, Craig RK, Marshall I. Postjunctional inhibition of contractor responses in the mouse vas deferens by rat and human calcitonin gene-related peptides (CGRP). Br J Pharmacol 1986;88: 173–180.PubMedGoogle Scholar
  27. 27.
    Tarabal O, Calderó J, Ribera J, et al. Regulation of motoneuronal calcitonin gene-related peptide (CGRP) during axonal growth and neuromuscular synaptic plasticity induced by botulinum toxin in rats. Eur J Neurosci 1996;8: 829–836.PubMedCrossRefGoogle Scholar
  28. 28.
    Tsukiji J, Sango K, Udaka N, et al. Long-term induction of β-CGRP mRNA in rat lungs by allergic inflammation. Life Sci 2004;76: 163–177.PubMedCrossRefGoogle Scholar
  29. 29.
    Ren YH, Qin XQ, Guan CX, Luo ZQ, Zhang CQ, Sun XH. Temporal and spatial distribution of VIP, CGRP and their receptors in the development of airway hyperresponsiveness in the lungs. Sheng Li Xue Bao 2004;56: 137–146.PubMedGoogle Scholar
  30. 30.
    Kang JM, Kim N, Kim B, et al. Gastroprotective action of cochinchina momordica seed extract is mediated by activation of CGRP and inhibition of cPLA2/5-LOX pathway. Dig Dis Sci 2009;54: 2549–2560.CrossRefGoogle Scholar
  31. 31.
    Rasmussen TN, Schmidt P, Poulsen SS, Holst JJ. Effect of calcitonin gene-related peptide (CGRP) on motility and on the release of substance P, neurokinin A, somatostatin and gastrin in the isolated perfused porcine antrum. Neurogastroenterol Motil 2001;13: 353–359.PubMedCrossRefGoogle Scholar
  32. 32.
    Zhang Z, Winborn CS, Marquez de Prado B, Russo AF. Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci 2007;27: 2693–2703.PubMedCrossRefGoogle Scholar
  33. 33.
    Thalakoti S, Patil VV, Damodaram S, et al. Neuron-glia signaling in trigeminal ganglion: implications for migraine pathology. Headache 2007;47: 1008–1023; discussion 1024-1005.PubMedCrossRefGoogle Scholar
  34. 34.
    Li J, Vause CV, Durham PL. Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Res 2008;1196: 22–32.PubMedCrossRefGoogle Scholar
  35. 35.
    Li XF, Kinsey-Jones JS, Bowe JE, et al. A role for the medial preoptic area in CGRP-induced suppression of pulsatile LH secretion in the female rat. Stress 2009;12: 259–267.PubMedCrossRefGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    McCulloch J, Uddman R, Kingman TA, Edvinsson L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A 1986;83: 5731–5735.PubMedCrossRefGoogle Scholar
  38. 38.
    Edvinsson L. Blockade of CGRP receptors in the intracranial vasculature: a new target in the treatment of headache. Cephalalgia 2004: 24: 611–622.PubMedCrossRefGoogle Scholar
  39. 39.
    Jansen-Olesen I, Mortensen A, Edvinsson L. Calcitonin generelated peptide is released from capsaicin-sensitive nerve fibres and induces vasodilatation of human cerebral arteries concomitant with activation of adenylyl cyclase. Cephalalgia 1996;16: 310–316.PubMedCrossRefGoogle Scholar
  40. 40.
    Edvinsson L, Jansen I, Kingman TA, McCulloch J. Cerebrovascular responses to capsaicin in vitro and in situ. Br J Pharmacol 1990;100: 312–318.PubMedGoogle Scholar
  41. 41.
    Grant AD, Pinter E, Salmon AM, Brain SD. An examination of neurogenic mechanisms involved in mustard oil-induced inflammation in the mouse. Eur J Pharmacol 2005;507: 273–280.PubMedCrossRefGoogle Scholar
  42. 42.
    Petersen KA, Birk S, Doods H, Edvinsson L, Olesen J. Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat. Br J Pharmacol 2004;143: 697–704.PubMedCrossRefGoogle Scholar
  43. 43.
    Goadsby PJ, Edvinsson L. Joint 1994 Wolff Award Presentation. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90. Headache 1994;34: 394–399.PubMedCrossRefGoogle Scholar
  44. 44.
    Mayberg M, Langer RS, Zervas NT, Moskowitz MA. Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science 1981;213: 228–230.PubMedCrossRefGoogle Scholar
  45. 45.
    Edvinsson L, Hara H, Uddman R. Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides. J Cereb Blood Flow Metab 1989;9: 212–218.PubMedGoogle Scholar
  46. 46.
    Uddman R, Hara H, Edvinsson L. Neuronal pathways to the rat middle meningeal artery revealed by retrograde tracing and immunocytochemistry. J Auton Nerv Syst 1989;26: 69–75.PubMedCrossRefGoogle Scholar
  47. 47.
    Liu Y, Broman J, Edvinsson L. Central projections of sensory innervation of the rat superior sagittal sinus. Neuroscience 2004;129: 431–437.PubMedCrossRefGoogle Scholar
  48. 48.
    Edvinsson L, Uddman R. Neurobiology in primary headaches. Brain Res Brain Res Rev 2005;48: 438–456.PubMedCrossRefGoogle Scholar
  49. 49.
    Tran Dinh YR, Thurel C, Serrie A, Cunin G, Seylaz J. Glycerol injection into the trigeminal ganglion provokes a selective increase in human cerebral blood flow. Pain 1991;46: 13–16.PubMedCrossRefGoogle Scholar
  50. 50.
    Goadsby PJ, Edvinsson L, Ekman R. Cutaneous sensory stimulation leading to facial flushing and release of calcitonin generelated peptide. Cephalalgia 1992;12: 53–56.PubMedCrossRefGoogle Scholar
  51. 51.
    Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28: 183–187.PubMedCrossRefGoogle Scholar
  52. 52.
    Pietrobon D. Migraine: new molecular mechanisms. Neuroscientist 2005;11: 373–386.PubMedCrossRefGoogle Scholar
  53. 53.
    Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87: 543–552.PubMedCrossRefGoogle Scholar
  54. 54.
    van de Ven RC, Kaja S, Plomp JJ, et al. Genetic models of migraine. Arch Neurol 2007;64: 643–646.PubMedCrossRefGoogle Scholar
  55. 55.
    Woods RP, Iacoboni M, Mazziotta JC. Brief report: bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994;331: 1689–1692.PubMedCrossRefGoogle Scholar
  56. 56.
    Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001;98: 4687–4692.PubMedCrossRefGoogle Scholar
  57. 57.
    Welch KM, Cao Y, Aurora S, Wiggins G, Vikingstad EM. MRI of the occipital cortex, red nucleus, and substantia nigra during visual aura of migraine. Neurology 1998;51;1465–1469.PubMedGoogle Scholar
  58. 58.
    Cao Y, Aurora SK, Nagesh V, Patel SC, Welch KM. Functional MRI-BOLD of brainstem structures during visually triggered migraine. Neurology 2002;59: 72–78.PubMedGoogle Scholar
  59. 59.
    Edvinsson L, Degueurce A, Duverger D, MacKenzie ET, Scatton B. Central serotonergic nerves project to the pial vessels of the brain. Nature 1983;306: 55–57.PubMedCrossRefGoogle Scholar
  60. 60.
    Olesen J, Thomsen LL, Iversen H. Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci 1994;15: 149–153.PubMedCrossRefGoogle Scholar
  61. 61.
    Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 2005;25: 179–183.PubMedCrossRefGoogle Scholar
  62. 62.
    Juhasz G, Zsombok T, Modos EA, 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.PubMedCrossRefGoogle Scholar
  63. 63.
    Kruuse C, Iversen H, Jansen-Olesen I, Edvinsson L, Olesen J. Calcitonin gene-related peptide (CGRP) levels during glyceryl trinitrate (GTN)-induced headache in healthy volunteers. Cephalalgia 2009 Aug 11 [Epub ahead of print].Google Scholar
  64. 64.
    Stepień A, Jagustyn P, Trafny EA, Widerkiewicz K. Suppressing effect of the serotonin 5HT1B/D receptor agonist rizatriptan on calcitonin gene-related peptide (CGRP) concentration in migraine attacks [In Polish]. Neurol Neurochir Pol 2003;37: 1013–1023.PubMedGoogle Scholar
  65. 65.
    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: 561–568.PubMedCrossRefGoogle Scholar
  66. 66.
    Juul R, Edvinsson L, Gisvold SE, Ekman R, Brubakk AO, Fredriksen TA. Calcitonin gene-related peptide-LI in subarachnoid haemorrhage in man: signs of activation of the trigeminocerebrovascular system? Br J Neurosurg 1990;4: 171–179.PubMedCrossRefGoogle Scholar
  67. 67.
    Juul R, Hara H, Gisvold SE, et al. Alterations in perivascular dilatory neuropeptides (CGRP, SP, VIP) in the external jugular vein and in the cerebrospinal fluid following subarachnoid haemorrhage in man. Acta Neurochir (Wien) 1995;132: 32–41.CrossRefGoogle Scholar
  68. 68.
    Smith D, Hill RG, Edvinsson L, Longmore J. An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres. Cephalalgia 2002;22: 424–431.PubMedCrossRefGoogle Scholar
  69. 69.
    Nilsson T, et al. Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol 1999;372: 49–56.PubMedCrossRefGoogle Scholar
  70. 70.
    Waugh DJ, Bockman CS, Smith DD, Abel PW. Limitations in using peptide drugs to characterize calcitonin gene-related peptide receptors. J Pharmacol Exp Ther 1999;289: 1419–1426.PubMedGoogle Scholar
  71. 71.
    McLatchie LM, Fraser NJ, Main MJ, et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1998;393: 333–339.PubMedCrossRefGoogle Scholar
  72. 72.
    Foord SM, Marshall FH. RAMPs: accessory proteins for seven transmembrane domain receptors. Trends Pharmacol Sci 1999;20: 184–187.PubMedCrossRefGoogle Scholar
  73. 73.
    Hay DL, Poyner DR, Quirion R; International Union of Pharmacology. International Union of Pharmacology. LXIX. Status of the calcitonin gene-related peptide subtype 2 receptor. Pharmacol Rev 2008;60: 143–145.PubMedCrossRefGoogle Scholar
  74. 74.
    Oliver KR, Wainwright A, Edvinsson L, Pickard JD, Hill RG. Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature. J Cereb Blood Flow Metab 2002;22: 620–629.PubMedCrossRefGoogle Scholar
  75. 75.
    Lennerz JK, Rühle V, Ceppa EP, et al. 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 2008;507: 1277–1299.PubMedCrossRefGoogle Scholar
  76. 76.
    Petersen KA, Nilsson E, Olesen J, Edvinsson L. Presence and function of the calcitonin gene-related peptide receptor on rat pial arteries investigated in vitro and in vivo. Cephalalgia 2005;25: 424–432.PubMedCrossRefGoogle Scholar
  77. 77.
    Edvinsson L, Cantera L, Jansen-Olesen I, Uddman R. Expression of calcitonin gene-related peptide1 receptor mRNA in human trigeminal ganglia and cerebral arteries. Neurosci Lett 1997;229: 209–211.PubMedCrossRefGoogle Scholar
  78. 78.
    Sams A, Jansen-Olesen I. Expression of calcitonin receptor-like receptor and receptor-activity-modifying proteins in human cranial arteries. Neurosci Lett 1998;258: 41–44.PubMedCrossRefGoogle Scholar
  79. 79.
    Doods H, Hallermayer G, Wu D, et al. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 2000;129: 420–423.PubMedCrossRefGoogle Scholar
  80. 80.
    Edvinsson L, Sams A, Jansen-Olesen I, et al. Characterisation of the effects of a non-peptide CGRP receptor antagonist in SK-N-MC cells and isolated human cerebral arteries. Eur J Pharmacol 2001;415: 39–44.PubMedCrossRefGoogle Scholar
  81. 81.
    Verheggen R, Bumann K, Kaumann AJ. BIBN4096BS is a potent competitive antagonist of the relaxant effects of α-CGRP on human temporal artery: comparison with CGRP8–37. Br J Pharmacol 2002;136: 120–126.PubMedCrossRefGoogle Scholar
  82. 82.
    Edvinsson L, Alm R, Shaw D, et al. Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells. Eur J Pharmacol 202;434:49–53.Google Scholar
  83. 83.
    Mallee JJ, Salvatore CA, LeBourdelles B, et al. Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists. J Biol Chem 2002;277: 14294–14298.PubMedCrossRefGoogle Scholar
  84. 84.
    Edvinsson L, McCulloch J, Kingman T, Uddman R. On the functional role of the trigemino-cerebrovascular system in the regulation of cerebral circulation. In: Owman C, Hardebo JE, editors. Neural regulation of the cerebral circulation. Amsterdam: Elsevier Science, 1986: 407–418.Google Scholar
  85. 85.
    Petersen KA, Birk S, Lassen LH, et al. The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers. Cephalalgia 2005;25: 139–147.PubMedCrossRefGoogle Scholar
  86. 86.
    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.PubMedCrossRefGoogle Scholar
  87. 87.
    Edvinsson L, Nilsson E, Jansen-Olesen I. Inhibitory effect of BIBN4096BS, CGRP(8–37), a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery. Br J Pharmacol 2007;150: 633–640.PubMedCrossRefGoogle Scholar
  88. 88.
    Olesen J, Diener HC, Husstedt IW, et al.; BIBN 4096 BS Clinical Roof of Concept Study Group. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004;350: 1104–1110.PubMedCrossRefGoogle Scholar
  89. 89.
    Salvatore CA, Hersey JC, Corcoran HA, et al. Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-l-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl) piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J Pharmacol Exp Ther 2008;324: 416–421.PubMedCrossRefGoogle Scholar
  90. 90.
    Chan KY, Edvinsson L, Eftekhari S, et al. Characterization of the CGRP receptor antagonist telcagepant in human isolated cerebral and meningeal arteries. Cephalalgia 2009;29 Suppl 1: 131 (Abstract PO311).Google Scholar
  91. 91.
    Sinclair S, et al. The novel oral CGRP antagonist, MK-0974, exhibits similar pharmacokinetics during and between migraine attacks. Cephalalgia 2007;27(Suppl 1): 738 (abstract).Google Scholar
  92. 92.
    Han TH, Blanchard RL, Palcza J, et al. Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults. J Clin Pharmacol 2010 Feb 19 [Epub ahead of print].Google Scholar
  93. 93.
    de Hoon J, et al. Lack of significant pharmacodynamic interaction between telcagepant 600 mg and sumatriptan 100 mg. Cephalalgia 2009;29: 1349 (abstract).Google Scholar
  94. 94.
    Ho TW, Mannix LK, Fan X, et al.; MK-0974 Protocol 004 Study Group. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008;70: 1304–1312.PubMedCrossRefGoogle Scholar
  95. 95.
    Ho TW, Ferrari MD, Dodick DW, 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: 2115–2123.PubMedCrossRefGoogle Scholar
  96. 96.
    Ho AP, Dahlof CGH, Silberstein SD, et al. Randomized, controlled, trial of telcagepant over four migraine attacks. Cephalalgia 2010 (in press).Google Scholar
  97. 97.
    Ho T, Connor K, Dahlof C, et al. Assessment of the long term safety and tolerability of telcagepant for the intermittent treatment of acute migraine: a double-blind, active-controlled study. Cephalalgia 2009;29 Suppl 1: 12 (Abstract PO03).Google Scholar
  98. 98.
    Connor KM, Shapiro RE, Diener HC, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 2009;73: 970–977.PubMedCrossRefGoogle Scholar
  99. 99.
    Sur C, Hargreaves R, Bell I, et al. CSF levels and binding pattern of novel CGRP receptor antagonists in rhesus monkey and human central nervous system: toward the development of a PET tracer. Cephalalgia 2009;29 Suppl 1: 136–137 (Abstract PO326).Google Scholar
  100. 100.
    Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol 2004;142: 1171–1181.PubMedCrossRefGoogle Scholar
  101. 101.
    Fischer MJ, Koulchitsky S, Messlinger K. The nonpeptide calcitonin gene-related peptide receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal trigeminal nucleus. J Neurosci 2005;25: 5877–5883.PubMedCrossRefGoogle Scholar
  102. 102.
    Di Angelantonio S, Giniatullin R, Costa V, Sokolova E, Nistri A. Modulation of neuronal nicotinic receptor function by the neuropeptides CGRP and substance P on autonomic nerve cells. Br J Pharmacol 2003;139: 1061–1073.PubMedCrossRefGoogle Scholar
  103. 103.
    Yu Y, Lundeberg T, Yu LC. Role of calcitonin gene-related peptide and its antagonist on the evoked discharge frequency of wide dynamic range neurons in the dorsal hom of the spinal cord in rats. Regul Pept 2002;103: 23–27.PubMedCrossRefGoogle Scholar
  104. 104.
    Giniatullin R, Nistri A, Fabbretti E. Molecular Mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol Neurobiol 2008;37: 83–90.PubMedCrossRefGoogle Scholar
  105. 105.
    Sun RQ, Lawand NB, Willis WD. The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin. Pain 2003;104: 201–208.PubMedCrossRefGoogle Scholar
  106. 106.
    Liu Y, Broman J, Edvinsson L. Central projections of the sensory innervation of the rat middle meningeal artery. Brain Res 2008;1208: 103–110.PubMedCrossRefGoogle Scholar
  107. 107.
    Morara S, Wang LP, Filippov V, et al. Calcitonin gene-related peptide (CGRP) triggers Ca2+ responses in cultured astrocytes and in Bergmann glial cells from cerebellar slices. Eur J Neurosci 2008;28: 2213–2220.PubMedCrossRefGoogle Scholar
  108. 108.
    Morara S, van der Want JJ, de Weerd H, Provini L, Rosina A. Ultrastructural analysis of climbing fiber-Purkinje cell synaptogenesis in the rat cerebellum. Neuroscience 2001;108: 655–671.PubMedCrossRefGoogle Scholar
  109. 109.
    Morara S, Rosina A, Provini L, Forloni G, Caretti A, Wimalawansa SJ. Calcitonin gene-related peptide receptor expression in the neurons and glia of developing rat cerebellum: an autoradiographic and immunohistochemical analysis. Neuroscience 2000;100: 381–391.PubMedCrossRefGoogle Scholar
  110. 110.
    Sándor PS, Mascia A, Scidel L, de Pasqua V, Schoenen J. Sub-clinical cerebellar impairment in the common types of migraine: a three-dimensional analysis of reaching movements. Ann Neurol 2001;49: 668–672.PubMedCrossRefGoogle Scholar
  111. 111.
    Brighina F, Palermo A, Panetta ML, et al. Reduced cerebellar inhibition in migraine with aura: a TMS study. Cerebellum 2009;8: 260–266.PubMedCrossRefGoogle Scholar
  112. 112.
    Pecile A, Guidobono F, Netti C, Sibilia V, Biella G, Braga PC. Calcitonin gene-related peptide: antinociceptive activity in rats, comparison with calcitonin. Regul Pept 1987;18: 189–199.PubMedCrossRefGoogle Scholar
  113. 113.
    Huang Y, Brodda-Jansen G, Lundeberg T, Yu LC. Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone. Brain Res 2000;873: 54–59.PubMedCrossRefGoogle Scholar
  114. 114.
    Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials [Erratum in: Cephalalgia 2003; 23:71]. Cephalalgia 2002;22: 633–658.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  1. 1.Department of Medicine, Institute of Clinical SciencesLund University Hospital, Lund UniversityLundSweden
  2. 2.Department of NeuroscienceMerck Research LaboratoriesNorth Wales

Personalised recommendations