Mechanisms of Migraine and Its Treatment

  • Lars Edvinsson
  • Antoinette Maassen van den Brink
  • Carlos M. Villalón
Reference work entry


Migraine is characterized by recurrent unilateral headaches, accompanied by nausea, vomiting, photophobia, and/or phonophobia, and in some cases facial symptoms. Current theories suggest that the initiation of a migraine attack involves a primary CNS event, putatively involving mutations in ion channels that render the individuals more sensitive to environmental factors, resulting in a wave of cortical spreading depression when the attack is initiated. Early positron emission tomography (PET) suggested the involvement of a migraine active region in the brainstem. In migraine attacks, data suggest that the pain is associated with the activation of the trigeminal nerve and the release of calcitonin gene-related peptide (CGRP) from the trigeminovascular system. Administration of triptans (5-HT1B/1D receptor agonists) causes the headache to subside and the levels of CGRP to normalize. Administration of CGRP receptor antagonists aborts the headache by specifically blocking the CGRP receptors located within the trigeminovascular system. Modern acute migraine therapy involves modulation of both CGRP and 5-HT1B/1D receptors.


Cluster Headache Migraine Attack Dura Mater Trigeminal Ganglion Migraine With Aura 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The studies of the authors reviewed here have in part been supported by the Swedish Research Council (project no. 5958).


  1. Arbab MA, Delgado T, Wiklund L, Svendgaard NA (1988) Brain stem terminations of the trigeminal and upper spinal ganglia innervation of the cerebrovascular system: WGA-HRP transganglionic study. J Cereb Blood Flow Metab 8:54–63PubMedGoogle Scholar
  2. Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J (2000) Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain 86:133–138PubMedGoogle Scholar
  3. Bahra A, Matharu MS, Buchel C, Frackowiak RS, Goadsby PJ (2001) Brainstem activation specific to migraine headache. Lancet 357:1016–1017PubMedGoogle Scholar
  4. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA (2002) Intrinsic brain activity triggers trgeminal meningeal afferents in a migraine model. Nat Med 8(2):136–142PubMedGoogle Scholar
  5. Bradley SR, Pieribone VA, Wang W, Severson CA, Jacobs RA, Richerson GB (2002) Chemosensitive serotonergic neruons are closely associated with large medullary arteries. Nat Neurosci 5:401–402PubMedGoogle Scholar
  6. Burstein R, Yamamura H, Malick A, Strassman AM (1998) Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol 79:964–982PubMedGoogle Scholar
  7. Cady RK, Vause CV, Ho TW, Bigal ME, Durham PL (2009) Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Headache 49:1258–1266PubMedGoogle Scholar
  8. Castro ME, Pascual J, Romon T, del Arco C, del Olmo E, Pazos A (1997) Differential distribution of [3H]sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F receptors) in human brain: focus on brainstem and spinal cord. Neuropharmacology 36:535–542PubMedGoogle Scholar
  9. Christiansen T, Bruun A, Knight YE, Goadsby PJ, Edvinsson L (2003) Immunoreactivity of NOS, CGRP, PACAP, SP and VIP in the trigeminal nucleus caudalis and in the cervical spinal cord C1and C2 of the cat. J Headache Pain 4:156–163Google Scholar
  10. Cohen Z, Bonvento G, Lacombe P, Hamel E (1996) Serotonin in the regulation of brain microcirculation. Prog Neurobiol 50:335–362PubMedGoogle Scholar
  11. Edvinsson L (2004) Blockade of CGRP receptors in the intracranial vasculature: a new target in the treatment of headache. Cephalalgia 24:611–622PubMedGoogle Scholar
  12. Edvinsson L (2008) CGRP blockers in migraine therapy: where do they act? Br J Pharmacol 155:967–969PubMedGoogle Scholar
  13. Edvinsson L (2009) Migraine: telcagepant provides new hope for people with migraine. Nat Rev Neurol 5:240–242PubMedGoogle Scholar
  14. Edvinsson L, Krause DN (2002) Cerebral blood flow and metabolism. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  15. Edvinsson L, Uddman R (2005) Neurobiology in primary headaches. Brain Res Brain Res Rev 48:438–456PubMedGoogle Scholar
  16. Edvinsson L, Nielsen KC, Owman C, Sporrong B (1972) Cholinergic mechanisms in pail vessels. Histochmistry, electron microscopy and pharmacology. Z Zellforsch Mikrosk Anat 134:311–325PubMedGoogle Scholar
  17. Edvinsson L, Falck B, Owman C (1977) Possibilities for a cholinergic action on smooth musculature and on sympathetic axons in brain vessels mediated by muscarinic and nicotinic receptors. J Pharmacol Exp Ther 200:117–126PubMedGoogle Scholar
  18. Edvinsson L, McCulloch J, Uddman R (1981) Substance P: immunohistochemical localization and effect upon cat pial arteries in vitro and in situ. J Physiol 318:251–258PubMedGoogle Scholar
  19. Edvinsson L, Degueurce A, Duverger D, MacKenzie ET, Scatton B (1983) Central serotonergic nerves project to the pial vessels of the brain. Nature 306:55–57PubMedGoogle Scholar
  20. 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 7:720–728PubMedGoogle Scholar
  21. Edvinsson L, Hara H, Uddman R (1989) Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides. J Cereb Blood Flow Metab 9:212–218PubMedGoogle Scholar
  22. Edvinsson L, Jansen I, Kingman TA, McCulloch J (1990) Cerebrovascular responses to capsaicin in vitro and in situ. Br J Pharmacol 100:312–318PubMedGoogle Scholar
  23. Edvinsson L, Jansen Olesen I, Kingman TA, McCulloch J, Uddman R (1995) Modification of vasoconstrictor responses in cerebral blood vessels by lesioning of the trigeminal nerve: possible involvement of CGRP. Cephalalgia 15:373–383PubMedGoogle Scholar
  24. Edvinsson L, Gulbenkian S, Barroso CP, Cunhae Sa M, Polak JM, Mortensen A et al (1998a) Innervation of the human middle meningeal artery: immunohistochemistry, ultrastructure, and role of endothelium for vasomotility. Peptides 19:1213–1225PubMedGoogle Scholar
  25. Edvinsson L, Mulder H, Goadsby PJ, Uddman R (1998b) 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 70:15–22PubMedGoogle Scholar
  26. Edvinsson L, Elsås T, Suzuki N, Shimizu T, Lee TJ (2001) Origin and Co-localization of nitric oxide synthase, CGRP, PACAP, and VIP in the cerebral circulation of the rat. Microsc Res Tech 53:221–228PubMedGoogle Scholar
  27. Edvinsson L, Alm R, Shaw D, Rutledge RZ, Koblan KS, Longmore J et al (2002) Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells. Eur J Pharmacol 434:49–53PubMedGoogle Scholar
  28. Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S (1995) Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 60:119–123PubMedGoogle Scholar
  29. Fanciullacci M, Alessandri M, Sicuteri R, Marabini S (1997) Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients. Brain 120(Pt 2):283–288PubMedGoogle Scholar
  30. Fields HL, Basbaum AI (1994) Central nervous system mechanisms of pain modulation. In: Wall PD, Melzack R (eds) Textbook of pain. Churcill Livingstone, EdinburghGoogle Scholar
  31. 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):47–54PubMedGoogle Scholar
  32. Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Glioti G et al (1995) Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 15:384–390PubMedGoogle Scholar
  33. Goadsby PJ, Edvinsson L (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33:48–56PubMedGoogle Scholar
  34. Goadsby PJ, Edvinsson L (1994) Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 117(Pt 3):427–434PubMedGoogle Scholar
  35. Goadsby PJ, Hoskin KL (1997) The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J Anat 190:367–375PubMedGoogle Scholar
  36. Goadsby PJ, Zagami AS (1991) Stimulation of the superior sagittal sinus increases metabolic activity and blood flow in certain regions of the brainstem and upper cervical spinal cord of the cat. Brain 114:1001–1011PubMedGoogle Scholar
  37. 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 23:193–196PubMedGoogle Scholar
  38. 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
  39. Goadsby PJ, Uddman R, Edvinsson L (1996) Cerebral vasodilatation in the cat involves nitric oxide from parasympathetic nerves. Brain Res 707:110–118PubMedGoogle Scholar
  40. Goadsby PJ, Lipton RB, Ferrari MD (2002) Migraine–current understanding and treatment. N Engl J Med 346:257–270PubMedGoogle Scholar
  41. Goldstein DJ, Wang O, Saper JR, Stoltz R, Silberstein SD, Mathew NT (1997) Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia 17:785–790PubMedGoogle Scholar
  42. Gulbenkian S, Uddman R, Edvinsson L (2001) Neuronal messengers in the human cerebral circulation. Peptides 22:995–1007PubMedGoogle Scholar
  43. Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B et al (2001) Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 98:4687–4692PubMedGoogle Scholar
  44. Hara H, Hamill GS, Jacobowithz DM (1985) Origin of cholinergic nerves to the rat major cerebral arteries: coexistence with vasoactive intestinal polypeptide. Brain Res Bull 25:179–188Google Scholar
  45. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X et al (2008) 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 372:2115–2123PubMedGoogle Scholar
  46. Hoffmann J, Neeb L, Israel H, Dannenberg F, Triebe F, Dirnagl U et al (2009) Intracisternal injection of inflammatory soup activates the trigeminal nerve system. Cephalalgia 29:1212–1217PubMedGoogle Scholar
  47. Holthusen H, Kindgen-Milles D, Ding ZP (1997) Substance P is not involved in vascular nociception in humans. Neuropeptides 31:445–448PubMedGoogle Scholar
  48. Honey AC, Bland-Ward PA, Connor HE, Feniuk W, Humphrey PPA (2002) Study of an adenosine A1 receptor agonist on trigeminally evoked dural blood vessel dilation in the anaesthetized rat. Cephalalgia 22:260–264PubMedGoogle Scholar
  49. Hoskin KL, Zagami AS, Goadsby PJ (1999) Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat. J Anat 194:579–588PubMedGoogle Scholar
  50. Hou M, Kanje M, Longmore J, Tajti J, Uddman R, Edvinsson L (2001) 5-HT(1B) and 5-HT(1D) receptors in the human trigeminal ganglion: co-localization with calcitonin gene-related peptide, substance P and nitric oxide synthase. Brain Res 909:112–120PubMedGoogle Scholar
  51. Jansen I, Alafaci C, McCulloch J, Uddman R, Edvinsson L (1991) Tachykinins (substance P, neurokinin A, neuropeptide K, and neurokinin B) in the cerebral circulation: vasomotor responses in vitro and in situ. J Cereb Blood Flow Metab 11:567–575PubMedGoogle Scholar
  52. Jansen-Olesen I, Goadsby PJ, Uddman R, Edvinsson L (1994) Vasoactive intestinal peptide (VIP) like peptides in the cerebral circulation of the cat. J Auton Nerv Syst 49(Suppl):S97–S103PubMedGoogle Scholar
  53. Juhasz G, Zsombok T, Modos EA, Olajos S, Jakab B, Nemeth J 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. Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G (2005) Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 25:179–183PubMedGoogle Scholar
  55. Kaube H, Keay KA, Hoskin KL, Bandler R, Goadsby PJ (1993) Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following stimulation of the superior sagittal sinus in the cat. Brain Res 629:95–102PubMedGoogle Scholar
  56. Knyihar-Csillik E, Tajti J, Samsam M, Sary G, Slezak S, Vecsei L (1997) Effect of a serotonin agonist (sumatriptan) on the peptidergic innervation of the rat cerebral dura mater and on the expression of c-fos in the caudal trigeminal nucleus in an experimental migraine model. J Neurosci Res 48:449–464PubMedGoogle Scholar
  57. Knyihar-Csillik E, Tajti J, Csillik AE, Chadaide Z, Mihaly A, Vecsei L (2000) Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion, and on the expression of c-fos and c-jun in the trigeminal complex of the rat in an experimental migraine model. Eur J Neurosci 12:3991–4002PubMedGoogle Scholar
  58. Kruuse C, Iversen HK, Jansen-Olesen I, Edvinsson L, Olesen J (2010) Calcitonin gene-related peptide (cgrp) levels during glyceryl trinitrate (gtn)-induced headache in healthy volunteers. Cephalalgia 30(4):467–474PubMedGoogle Scholar
  59. Lauritzen M (1994) Pathophysiology of the migraine aura. The spreading depression theory. Brain 117(Pt 1):199–210PubMedGoogle Scholar
  60. Lee TJ (1980) Direct evidence against acetylcholine as the dilator transmitter in the cat cerebral artery. Eur J Pharmacol 68:393–394PubMedGoogle Scholar
  61. Lee TJ (1982) Cholinergic mechanism in the large cat cerebral artery. Circ Res 50:870–879PubMedGoogle Scholar
  62. Lee TJ (2000) Nitric oxide and the cerebral vascular function. J Biomed Sci 7:16–26PubMedGoogle Scholar
  63. Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF 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
  64. 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 58:698–705PubMedGoogle Scholar
  65. Linde M, Mellberg A, Dahlof C (2006) The natural course of migraine attacks. A prospective analysis of untreated attacks compared with attacks treated with a triptan. Cephalalgia 26:712–721PubMedGoogle Scholar
  66. Liu Y, Broman J, Edvinsson L (2004) Central projections of sensory innervation of the rat superior sagittal sinus. Neuroscience 129:431–437PubMedGoogle Scholar
  67. Liu Y, Broman J, Edvinsson L (2008) Central projections of the sensory innervation of the rat middle meningeal artery. Brain Res 1208:103–110PubMedGoogle Scholar
  68. Longmore J, Shaw D, Smith D, Hopkins R, McAllister G, Pickard JD et al (1997) Differential distribution of 5HT1D- and 5HT1B-immunoreactivity within the human trigemino-cerebrovascular system: implications for the discovery of new antimigraine drugs. Cephalalgia 17:833–842PubMedGoogle Scholar
  69. 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
  70. May A, Goadsby PJ (1999) The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19:115–127PubMedGoogle Scholar
  71. McCulloch J, Uddman R, Kingman TA, Edvinsson L (1986) Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci USA 83:5731–5735PubMedGoogle Scholar
  72. Moller K, Zhang YZ, Hakanson R, Luts A, Sjolund B, Uddman R et al (1993) Pituitary adenylate cyclase activating peptide is a sensory neuropeptide: immunocytochemical and immunochemical evidence. Neuroscience 57:725–732PubMedGoogle Scholar
  73. Nielsen KC, Owman C (1967) Adrenergic innervation of pail arteries related to the circle of Willis in the cat. Brain Res 6(4):773–776PubMedGoogle Scholar
  74. Nozaki K, Moskowitz MA, Maynard KI, Koketsu N, Dawson TM, Bredt DS et al (1993) Possible origins and distribution of immunoreactive nitric oxide synthase-containing nerve fibers in cerebral arteries. J Cereb Blood Flow Metab 13:70–79PubMedGoogle Scholar
  75. Olesen J (2008) The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 120:157–171PubMedGoogle Scholar
  76. Olesen J, Friberg L, Olsen TS, Iversen HK, Lassen NA, Andersen AR et al (1990) Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol 28:791–798PubMedGoogle Scholar
  77. Olesen J, Thomsen LL, Lassen LH, Jansen-Olesen I (1995) The nitric oxide hypothesis of migraine and other vascular headaches. Cephalalgia 15:94–100PubMedGoogle Scholar
  78. Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U 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
  79. Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA (2006) The headaches, 3rd edn. Lipincott, Williams & Wilkins, PhiladelphiaGoogle Scholar
  80. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552PubMedGoogle Scholar
  81. Pascual J, Del Arco C, Romon T, Del Olmo E, Pazos A (1996) [3H]Sumatriptan binding sites in human brain: regional-dependent labelling of 5-HT1D and 5-HT1F receptors. Eur J Pharmacol 295:271–274PubMedGoogle Scholar
  82. Phebus LA, Johnson KW, Stengel PW, Lobb KL, Nixon JA, Hipskind PA (1997) The non-peptide NK-1 receptor antagonist LY303870 inhibits neurognic dural inflammation in guinea pigs. Life Sci 60:1553–1561PubMedGoogle Scholar
  83. Pietrobon D, Striessnig J (2003) Neurobiology of migraine. Nat Rev Neurosci 4:386–398PubMedGoogle Scholar
  84. 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 13:180–183PubMedGoogle Scholar
  85. Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M (2008) Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 28:226–236PubMedGoogle Scholar
  86. Ray B, Wolff H (1940) Experimental studies on headaches, pain sensitive structures of the heada and their significance in headaches. Arch Surg 41:813–856Google Scholar
  87. Saito A, Wu JY, Lee TJ (1985) Evidence for the presence of cholinergic nerves in cerebral arteries: an immunohistochemical demonstration of choline acetyltransferase. J Cereb Blood Flow Metab 10:399–408Google Scholar
  88. Salvatore CA, Hershey JC, Corcoran HA, Fay JF, Johnston VK, Moore EL 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
  89. 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 132:16–25PubMedGoogle Scholar
  90. Schytz HW, Wienecke T, Olesen J, Ashina M (2010) Carbachol induces headache, but not migraine-like attacks, in patients with migraine without aura. Cephalalgia 30:337–345PubMedGoogle Scholar
  91. Seki Y, Suzuki Y, Baskaya MK, Kano T, Saito K, Takayasu M et al (1995) The effects of pituitary adenylate cyclase-activating polypeptide on cerebral arteries and vertebral artery blood flow in anesthetized dogs. Eur J Pharmacol 275:259–266PubMedGoogle Scholar
  92. Shepheard SL, Williamson DJ, Hill RG, Hargreaves RJ (1993) The non-peptide neurokinin1 receptor antagonist, RP 67580, blocks neurogenic plasma extravasation in the dura mater of rats. Br J Pharmacol 108:11–12PubMedGoogle Scholar
  93. Shepheard SL, Williamson DJ, Williams J, Hill RG, Hargreaves RJ (1995) Comparison of the effects of sumatriptan and the NK1 antagonist CP-99, 994 on plasma extravasation in dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats. Neuropharmacology 34:255–261PubMedGoogle Scholar
  94. Shepheard S, Edvinsson L, Cumberbatch M, Williamson D, Mason G, Webb J et al (1999) Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370. Cephalalgia 19:851–858PubMedGoogle Scholar
  95. Stepien A, Jagustyn P, Trafny EA, Widerkiewicz K (2003) Suppressing effect of the serotonin 5HT1B/D receptor agonist rizatriptan on calcitonin gene-related peptide (CGRP) concentration in migraine attacks. Neurol Neurochir Pol 37:1013–1023PubMedGoogle Scholar
  96. Suzuki N, Hardebo JE, Owman C (1988) Origins and pathways of cerebrovascular vasoactive intestinal polypeptide-positive nerves in rat. J Cereb Blood Flow Metab 8:697–712PubMedGoogle Scholar
  97. Suzuki N, Hardebo JE, Owman C (1990) Origins and pathways of choline acetyltransferase=positive parasympathetic nerve fibers to crebral vessels in rat. J Cereb Blood Flow Metab 10:399–408PubMedGoogle Scholar
  98. Tajti J, Uddman R, Moller S, Sundler F, Edvinsson L (1999) Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst 76:176–183PubMedGoogle Scholar
  99. Terwindt GM, Ophoff RA, Haan J, Vergouwe MN, van Eijk R, Frants RR et al (1998) Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Neurology 50:1105–1110PubMedGoogle Scholar
  100. Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J (2005) No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol 58:561–568PubMedGoogle Scholar
  101. 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 62:131–136PubMedGoogle Scholar
  102. Uddman R, Goadsby PJ, Jansen I, Edvinsson L (1993) PACAP, a VIP-like peptide: immunohistochemical localization and effect upon cat pial arteries and cerebral blood flow. J Cereb Blood Flow Metab 13:291–297PubMedGoogle Scholar
  103. 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 22:112–116PubMedGoogle Scholar
  104. Villalón CM, Olesen J (2009) The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther 124:309–323PubMedGoogle Scholar
  105. Wahl M, Schilling L, Parsons AA, Kaumann A (1994) Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression. Brain Res 637:204–210PubMedGoogle Scholar
  106. Wang X, Fang Y, Liang J, Yin Z, Miao J, Luo N (2010) Selective inhibition of 5-ht7 receptor reduces cgrp release in an experimental model for migraine. Headache 50:579–587PubMedGoogle Scholar
  107. Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV et al (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1:658–660PubMedGoogle Scholar
  108. Wienecke T, Olesen J, Oturai PS, Ashina M (2009) Prostaglandin e2(pge2) induces headache in healthy subjects. Cephalalgia 29:509–519PubMedGoogle Scholar
  109. Wienecke T, Olesen J, Ashina M (2010) Prostaglandin i(2) (epoprostenol) triggers migraine-like attacks in migraineurs. Cephalalgia 30:179–190PubMedGoogle Scholar
  110. Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL (1997) Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Cephalalgia 17:518–524PubMedGoogle Scholar
  111. Zagami AS, Goadsby PJ, Edvinsson L (1990) Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides 16:69–75PubMedGoogle Scholar

Copyright information

© Lifting The Burden 2011

Authors and Affiliations

  • Lars Edvinsson
    • 1
  • Antoinette Maassen van den Brink
    • 2
  • Carlos M. Villalón
    • 3
  1. 1.Department of MedicineLund University HospitalLundSweden
  2. 2.Division of Vascular Medicine and Pharmacology, Department MedicineErasmus University Medical CenterRotterdamThe Netherlands
  3. 3.Departamento de FarmacobiologíaCinvestav-CoapaMéxicoMexico

Personalised recommendations