• Silvia Benemei
  • Paola Nicoletti
  • Jay G. Capone
  • Francesco De Cesaris
  • Pierangelo Geppetti
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 194)


Migraine is a neurovascular disorder which affects one fifth of the general population. Disability due to migraine is severe and involves patients from infancy through senescence and it is aggravated by the fact there is no complete cure. However, various drugs for the symptomatic or prophylactic treatment of the disease are available. Recently, better knowledge of the neurobiological and pharmacological aspects of a subset of trigeminal primary sensory neurons has provided key information for the development of effective molecules that specifically target the activation of the trigeminovascular system and may represent a significant advancement in the treatment of the disease. These novel antagonists block the receptor for the sensory neuropeptide calcitonin gene-related peptide (CGRP), which upon release from peripheral terminals of trigeminal perivascular neurons dilates cranial arterial vessels. Whether neurogenic vasodilatation is the major contributing factor to generate the pain and the associated symptoms of the migraine attack or whether other sites of action of CGRP receptor antagonists are responsible for the antimigraine effect of these compounds is the subject of current and intense research.


Neurogenic vadodilatation Calcitonin gene-related peptide Primary sensory neurons CGRP receptor 



The paper was supported in part by grants from Consorzio Ferrara Ricerche, Ferrara, and by Fondazione DEI-Onlus, Florence, Italy.


  1. Aiyar N, Daines RA, Disa J et al (2001) Pharmacology of SB-273779, a nonpeptide calcitonin gene-related peptide 1 receptor antagonist. J Pharmacol Exp Ther 296:768–775PubMedGoogle Scholar
  2. Alessandri-Haber N, Yeh JJ, Boyd AE et al (2003) Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39:497–511PubMedGoogle Scholar
  3. Amara SG, Arriza JL, Leff SE et al (1985) Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide. Science 229:1094–1097PubMedGoogle Scholar
  4. Baluk P, Bertrand C, Geppetti P et al (1995) NK1 receptors mediate leukocyte adhesion in neurogenic inflammation in the rat trachea. Am J Physiol 268:L263–L269PubMedGoogle Scholar
  5. Bandell M, Story GM, Hwang SW et al (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849–857PubMedGoogle Scholar
  6. Bautista DM, Jordt SE, Nikai T et al (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–1282PubMedGoogle Scholar
  7. Bautista DM, Siemens J, Glazer JM et al (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448:204–208PubMedGoogle Scholar
  8. Bevan S, Geppetti P (1994) Protons: small stimulants of capsaicin-sensitive sensory nerves. Trends Neurosci 17:509–512PubMedGoogle Scholar
  9. Boeglin D, Hamdan FF, Melendez RE et al (2007) Calcitonin gene-related peptide analogues with aza and indolizidinone amino acid residues reveal conformational requirements for antagonist activity at the human calcitonin gene-related peptide 1 receptor. J Med Chem 50:1401–1408PubMedGoogle Scholar
  10. Brain SD, Williams TJ (1989) Interactions between the tachykinins and calcitonin gene-related peptide lead to the modulation of oedema formation and blood flow in rat skin. Br J Pharmacol 97:77–82PubMedGoogle Scholar
  11. Brain SD, Williams TJ, Tippins JR et al (1985) Calcitonin gene-related peptide is a potent vasodilator. Nature 313:54–56PubMedGoogle Scholar
  12. Brazil P, Friedman A (1957) Further observations in craniovascular studies. Neurology 7:52–55PubMedGoogle Scholar
  13. Caterina MJ, Schumacher MA, Tominaga M et al (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824PubMedGoogle Scholar
  14. Caterina MJ, Rosen TA, Tominaga M et al (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398:436–441PubMedGoogle Scholar
  15. Chiba T, Yamaguchi A, Yamatani T et al (1989) Calcitonin gene-related peptide receptor antagonist human CGRP-(8–37). Am J Physiol Endocrinol Metab 256:E331–E335Google Scholar
  16. Chuang HH, Prescott ED, Kong H et al (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962PubMedGoogle Scholar
  17. Connor H, Bertin L, Gillies S et al (1998) The GR205171 clinical study group. Clinical evaluation of a novel, potent, CNS penetrating NK1 receptor antagonist in the acute treatment of migraine. Cephalalgia 18:392Google Scholar
  18. Cooper GJS, Willis AC, Clark A et al (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA 84:8628–8632PubMedGoogle Scholar
  19. Diener HC (2003) RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia 23:183–185PubMedGoogle Scholar
  20. Doods H (2001) Development of CGRP antagonists for the treatment of migraine. Curr Opin Investig Drugs 2:1261–1268PubMedGoogle Scholar
  21. Doods H, Hallermayer G, Wu D et al (2000) Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 129:420–423PubMedGoogle Scholar
  22. Doods H, Arndt K, Rudolf K et al (2007) CGRP antagonists: unravelling the role of CGRP in migraine. Trends Pharmacol Sci 28:580–587PubMedGoogle Scholar
  23. Durham PL (2004) CGRP-receptor antagonists – a fresh approach to migraine therapy? New Engl J Med 350:1073–1075PubMedGoogle Scholar
  24. Edvinsson L (2004) Blockade of CGRP receptors in the intracranial vasculature: a new target in the treatment of headache. Cephalalgia 24:611–622PubMedGoogle Scholar
  25. Edvinsson L, Sams A, Jansen-Olesen I et al (2001) Characterisation of the effects of a non-peptide CGRP receptor antagonist in SK-N-MC cells and isolated human cerebral arteries. Eur J Pharmacol 415:39–44PubMedGoogle Scholar
  26. Ennis MD, Ghazal NB, Hoffman RL et al (1998) Isochroman-6-carboxamides as highly selective 5-HT1D agonists: potential new treatment for migraine without cardiovascular side effects. J Med Chem 41:2180–2183PubMedGoogle Scholar
  27. Fanciullacci M, Tramontana M, Bianco ED et al (1991) Low pH medium induces calcium dependent release of CGRP from sensory nerves of guinea-pig dural venous sinuses. Life Sci 49:PL27–PL30PubMedGoogle Scholar
  28. Fanciullacci M, Alessandri M, Figini M et al (1995) Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 60:119–123PubMedGoogle Scholar
  29. Fay T (1935) The mechanism of headache. Trans Am Neurol Assoc 62:74–77Google Scholar
  30. Feindel W, Penfield W, Mc NF (1960) The tentorial nerves and localization of intracranial pain in man. Neurology 10:555–563PubMedGoogle Scholar
  31. Fernandez-Patron C, Stewart KG, Zhang Y et al (2000) Vascular matrix metalloproteinase-2-dependent cleavage of calcitonin gene-related peptide promotes vasoconstriction. Circ Res 87:670–676PubMedGoogle Scholar
  32. Ferrari MD, Saxena PR (1993) On serotonin and migraine: a clinical and pharmacological review. Cephalalgia 13:151–165PubMedGoogle Scholar
  33. Ferrari MD, Roon KI, Lipton RB et al (2001) Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 358:1668–1675PubMedGoogle Scholar
  34. Fluhmann B, Muff R, Hunziker W et al (1995) A human orphan calcitonin receptor-like structure. Biochem Biophys Res Commun 206:341–347PubMedGoogle Scholar
  35. Franco-Cereceda A (1991) Calcitonin gene-related peptide and human epicardial coronary arteries: presence, release and vasodilator effects. Br J Pharmacol 102:506–510PubMedGoogle Scholar
  36. Gazzieri D, Trevisani M, Springer J et al (2007) Substance P released by TRPV1-expressing neurons produces reactive oxygen species that mediate ethanol-induced gastric injury. Free Radic Biol Med. 43:581–589PubMedGoogle Scholar
  37. Geppetti P, Holzer P (1996) Neurogenic inflammation. CRC, Boca RatonGoogle Scholar
  38. Geppetti P, Del Bianco E, Cecconi R et al (1992) Capsaicin releases calcitonin gene-related peptide from the human iris and ciliary body in vitro. Regul Pept 41:83–92PubMedGoogle Scholar
  39. Giffin NJ, Kowacs F, Libri V et al (2003) Effect of the adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects. Cephalalgia 23:287–292PubMedGoogle Scholar
  40. Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28:183–187PubMedGoogle Scholar
  41. Goadsby PJ, Lipton RB, Ferrari MD (2002a) Migraine – current understanding and treatment. New Engl J Med 346:257–270PubMedGoogle Scholar
  42. Goadsby PJ, Hoskin KL, Storer RJ et al (2002b) Adenosine A1 receptor agonists inhibit trigeminovascular nociceptive transmission. Brain 125:1392–1401PubMedGoogle Scholar
  43. Goldstein DJ, Wang O, Saper JR et al (1997) Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia 17:785–790PubMedGoogle Scholar
  44. Goldstein J, Roon I, Offen W et al (1999) Migraine treatment with selective with 5-ht1F receptor agonist (SSOFRA) LY334370. Cephalalgia 19:318Google Scholar
  45. Gomez-Mancilla B, Cutler N, Leibowitz M et al (2001) Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine. Cephalalgia 21:727–732PubMedGoogle Scholar
  46. Graham J, Wolff H (1938) Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 39:737–763Google Scholar
  47. Gray DW, Marshall I (1992) Human alpha-calcitonin gene-related peptide stimulates adenylate cyclase and guanylate cyclase and relaxes rat thoracic aorta by releasing nitric oxide. Br J Pharmacol 107:691–696PubMedGoogle Scholar
  48. Ho TW, Mannix LK, Fan X et al (2007) Randomized controlled trial of an oral CGRP antagonist, MK-0974, in acute treatment of migraine. Neurology 70:1304–1312PubMedGoogle Scholar
  49. Huang SM, Bisogno T, Trevisani M et al (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci USA 99:8400–8405PubMedGoogle Scholar
  50. Humphrey PP, Bland-Ward PA, Carruthers AM et al (2001) Inhibition of trigemnial nociceptive afferents by adenosine A1 receptor activation: a novel approach towards the design of new anti-migraine compounds. Cephalalgia 21:268–269Google Scholar
  51. Hwang SW, Cho H, Kwak J et al (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA 97:6155–6156PubMedGoogle Scholar
  52. Jordt SE, Bautista DM, Chuang HH et al (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265PubMedGoogle Scholar
  53. Juhasz G, Zsombok T, Modos EA et al (2003) NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 106:461–470PubMedGoogle Scholar
  54. Kapoor K, Arulmani U, Heiligers JPC et al (2003) Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Br J Pharmacol 140:329–338PubMedGoogle Scholar
  55. Kitamura K, Kangawa K, Kawamoto M et al (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 192:553–560PubMedGoogle Scholar
  56. Knotkova H, Pappagallo M, Szallasi A (2008) Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival? Clin J Pain 24:142–154PubMedGoogle Scholar
  57. Lance J (1969) Mechanism and management of headache. Butterworths, New YorkGoogle Scholar
  58. Lassen LH, Haderslev PA, Jacobsen VB et al (2002) CGRP may play a causative role in migraine. Cephalalgia 22:54–61PubMedGoogle Scholar
  59. Lennerz JK, Ruhle V, Ceppa EP et al (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 507:1277–1299PubMedGoogle Scholar
  60. Lewis T (1937) The nocifensor system of nerves and its reactions. Br Med J 194:431–435Google Scholar
  61. Liedtke W, Choe Y, Marti-Renom MA et al (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525–535PubMedGoogle Scholar
  62. Macpherson LJ, Geierstanger BH, Viswanath V et al (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol 15:929–934PubMedGoogle Scholar
  63. Markowitz S, Saito K, Moskowitz MA (1987) Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain. J Neurosci 7:4129–4136PubMedGoogle Scholar
  64. McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58PubMedGoogle Scholar
  65. McLatchie LM, Fraser NJ, Main MJ et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339PubMedGoogle Scholar
  66. Morris HR, Panico M, Etienne T et al (1984) Isolation and characterization of human calcitonin gene-related peptide. Nature 308:746–748PubMedGoogle Scholar
  67. Moskowitz MA, Buzzi MG (1991) Neuroeffector functions of sensory fibres: implications for headache mechanisms and drug actions. J Neurol 238:S18–S22PubMedGoogle Scholar
  68. Mudderry PK, Ghatei MA, Spokes RA et al (1988) Differential expression of [alpha]-CGRP and [beta]-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience 25:195–205Google Scholar
  69. Nagata K, Duggan A, Kumar G et al (2005) Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci 25:4052–4061PubMedGoogle Scholar
  70. Nicoletti P, Trevisani M, Manconi M et al (2008) Ethanol causes neurogenic vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the guinea pig. Cephalalgia 28:9–17PubMedGoogle Scholar
  71. Nilius B, Owsianik G, Voets T et al (2007) Transient receptor potential cation channels in disease. Physiol Rev 87:165–217PubMedGoogle Scholar
  72. Njuki F, Nicholl CG, Howard A et al (1993) A new calcitonin-receptor-like sequence in rat pulmonary blood vessels. Clin Sci (Lond) 85:385–388Google Scholar
  73. Olesen J, Diener HC, Husstedt IW et al (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110PubMedGoogle Scholar
  74. Paone DV, Shaw AW, Nguyen DN et al (2007) Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: discovery of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974). J Med Chem 50:5564–5567PubMedGoogle Scholar
  75. Peier AM, Moqrich A, Hergarden AC et al (2002) A TRP channel that senses cold stimuli and menthol. Cell 108:705–715PubMedGoogle Scholar
  76. Penfield W, McNaughton M (1940) Dural headache and the innervation of the dura mater. Arch Neurol Psychiatr 44:43–75Google Scholar
  77. Petermann J, Born W, Chang J et al (1987) Identification in the human central nervous system, pituitary, and thyroid of a novel calcitonin gene-related peptide, and partial amino acid sequence in the spinal cord. J Biol Chem 262:542–545PubMedGoogle Scholar
  78. Petersen K, Birk S, Lassen L et al (2005) The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers. Cephalalgia 25:139–147PubMedGoogle Scholar
  79. Premkumar LS, Ahern GP (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature 408:985–990PubMedGoogle Scholar
  80. Quirion R, D Van Rossum, Dumont Y et al (1992) Characterization of CGRP1 and CGRP2 receptor subtypes. Ann N Y Acad Sci 657:88–105PubMedGoogle Scholar
  81. Raddino R, Pela G, Manca C et al (1997) Mechanism of action of human calcitonin gene-related peptide in rabbit heart and in human mammary arteries. J Cardiovasc Pharmacol 29:463–470PubMedGoogle Scholar
  82. Ramadan NM, Skljarevski V, Phebus LA et al (2003) 5-HT1F receptor agonists in acute migraine treatment: a hypothesis. Cephalalgia 23:776–785PubMedGoogle Scholar
  83. Ray B, Wolff H (1940) Experimental studies on headache: pain-sensitive structures of the head and their significance in headache. Arch Surg 41:813–856Google Scholar
  84. Salvatore CA, Hershey JC, Corcoran HA et al (2008) Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbox amide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J Pharmacol Exp Ther 324:416–421PubMedGoogle Scholar
  85. Schoonman GG, van der Grond J, Kortmann C et al (2008) Migraine headache is not associated with cerebral or meningeal vasodilatation – a 3T magnetic resonance angiography study. Brain 131:2192–2200PubMedGoogle Scholar
  86. Simone DA, Ochoa J (1991) Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans. Pain 47:285–294PubMedGoogle Scholar
  87. Smith D, Hill RG, Edvinsson L et al (2002) An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres. Cephalalgia 22:424–431PubMedGoogle Scholar
  88. Snider RM, Constantine JW, Lowe JA 3rd et al (1991) A potent nonpeptide antagonist of the substance P (NK1) receptor. Science 251:435–437PubMedGoogle Scholar
  89. Story GM, Peier AM, Reeve AJ et al (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829PubMedGoogle Scholar
  90. Struthers AD, Brown MJ, Macdonald DW et al (1986) Human calcitonin gene related peptide: a potent endogenous vasodilator in man. Clin Sci (Lond) 70:389–393Google Scholar
  91. Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–212PubMedGoogle Scholar
  92. Szolcsanyi J (1977) A pharmacological approach to elucidation of the role of different nerve fibres and receptor endings in mediation of pain. J Physiol 73:251–259Google Scholar
  93. Taylor CK, Smith DD, Hulce M et al (2006) Pharmacological characterization of novel alpha-calcitonin gene-related peptide (CGRP) receptor peptide antagonists that are selective for human CGRP receptors. J Pharmacol Exp Ther 319:749–757PubMedGoogle Scholar
  94. Tfelt-Hansen P, De Vries P, Saxena PR (2000) Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs 60:1259–1287PubMedGoogle Scholar
  95. Thomsen LL, Iversen HK, Brinck TA et al (1993) Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers. Cephalalgia 13:395–399PubMedGoogle Scholar
  96. Tominaga M, Caterina MJ, Malmberg AB et al (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543PubMedGoogle Scholar
  97. Trevisani M, Smart D, Gunthorpe MJ et al (2002) Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5:546–551PubMedGoogle Scholar
  98. Welch KMA (2003) Concepts of migraine headache pathogenesis: insights into mechanisms of chronicity and new drug targets. Neurol Sci 24:S149–S153PubMedGoogle Scholar
  99. Williamson DJ, Hill RG, Shepheard SL et al (2001) The anti-migraine 5-HT(1B/1D) agonist rizatriptan inhibits neurogenic dural vasodilation in anaesthetized guinea-pigs. Br J Pharmacol 133:1029–1034PubMedGoogle Scholar
  100. Wolff H (1948) Headache and other head pain. Oxford University Press, New York, pp 59–97Google Scholar
  101. Zygmunt PM, Petersson J, Andersson DA et al (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Silvia Benemei
    • 1
  • Paola Nicoletti
    • 1
  • Jay G. Capone
    • 1
  • Francesco De Cesaris
    • 1
  • Pierangelo Geppetti
    • 2
  1. 1.Centre for the Study of Headache and Department of Preclinical and Clinical PharmacologyUniversity of FlorenceFlorenceItaly
  2. 2.Headache CenterUniversity Hospital S. AnnaFerraraItaly

Personalised recommendations