1. Amara SG, Jonas V, Rosenfeld MG, Ong ES, et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 1982;298:240–4.
2. Arulmani U, Schuijt MP, Heiligers JP, Willems EW, et al. Effects of the calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS on alpha-CGRP-induced regional haemodynamic changes in anaesthetised rats. Basic Clin Pharmacol Toxicol 2004;94:291–7.
3. Beattie DT, Connor HE, Hagan RM. Recent developments in tachykinin NK1 receptor antagonists: prospects for the treatment of migraine. Can J Physiol Pharmacol 1995;73:871–7.
4. Bell D, McDermott BJ. Calcitonin gene-related peptide in the cardiovascular system: characterization of receptor populations and their (patho)physiological significance. Pharmacol Rev 1996;48:253–88.
5. Bellamy J, Bowen EJ, Russo AF, Durham PL. Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Eur J Neurosci 2006;23:2057–66.
6. Bigal ME, Dodick DW, Krymchantowski AV, VanderPluym JH, et al. TEV-48125 for the preventive treatment of chronic migraine: Efficacy at early time points. Neurology 2016;87:41–8.
7. Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015;14:1081–90.
8. Bigal ME, Escandon R, Bronson M, Walter S, et al. Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: Results of the Phase 1 program. Cephalalgia 2014;34:483–92.
9. Bigal ME, Walter S, Bronson M, Alibhoy A, et al. Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP. Cephalalgia 2014;34:968–76.
10. Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004;84:903–34.
11. Broome CS, Miyan JA. Neuropeptide control of bone marrow neutrophil production. A key axis for neuroimmunomodulation. Ann N Y Acad Sci 2000;917:424–34.
12. Bussone G, Diener H, Pfeil J, Schwalen S. Topiramate 100 mg/day in migraine prevention: a pooled analysis of double-blind randomised controlled trials. Int J Clin Pract 2005;59:961–8.
13. Buzzi MG, Carter WB, Shimizu THH, Moskowitz MA. Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology 1991;30:1193–200.
14. Buzzi MG, Moskowitz MA. Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine. Cephalalgia 1991;11:165–8.
15. Charbit AR, Akerman S, Holland PR, Goadsby PJ. Neurons of the dopaminergic/calcitonin gene-related peptide A11 cell group modulate neuronal firing in the trigeminocervical complex: an electrophysiological and immunohistochemical study. J Neurosci 2009;29:12532–41.
16. Cheret J, Lebonvallet N, Buhe V, Carre JL, et al. Influence of sensory neuropeptides on human cutaneous wound healing process. J Dermatol Sci 2014;74:193–203.
17. Connor KM, Aurora SK, Loeys T, Ashina M, et al. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache 2010;51:73–84.
18. Connor KM, Shapiro RE, Diener HC, Lucas S, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 2009;73:970–7.
19. Cottrell GS, Alemi F, Kirkland JG, Grady EF, et al. Localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in human gastrointestinal tract. Peptides 2012;35:202–11.
20. Covasala O, Stirn SL, Albrecht S, De Col R, et al. Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity. J Neurophysiol 2012;108:431–40.
21. Cui XP, Ye JX, Lin H, Mu JS, et al. Efficacy, safety, and tolerability of telcagepant in the treatment of acute migraine: a meta-analysis. Pain pract 2015;15:124–31.
22. Diener HC, Barbanti P, Dahlof C, Reuter U, et al. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 2010;31:573–84.
23. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014;13:1100–7.
24. Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, et al. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014;13:885–92.
25. Dux M, Rosta J, Santha P, Jancso G. Involvement of capsaicin-sensitive afferent nerves in the proteinase-activated receptor 2-mediated vasodilatation in the rat dura mater. Neuroscience 2009;161:887–94.
26. Edvinsson L, Ekman R, Jansen I, McCulloch J, et al. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J Cereb Blood Flow Metab 1987;7:720–8.
27. 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;150:633–40.
28. Edvinsson L, Villalon CM, MaassenVanDenBrink A. Basic mechanisms of migraine and its acute treatment. Pharmacol Ther 2012;136:319–33.
29. Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol 2015;80:193–9.
30. Eftekhari S, Gaspar RC, Roberts R, Chen TB, et al. 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 2016;524:90–118.
31. Eftekhari S, Salvatore CA, Calamari A, Kane SA, et al. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 2010;169:683–96.
32. Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 2013;14:1289–303.
33. Evans BN, Rosenblatt MI, Mnayer LO, Oliver KR, et al. CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem 2000;275:31438–43.
34. Fabbretti E, D‘Arco M, Fabbro A, Simonetti M, et al. Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J Neurosci 2006;26:6163–71.
35. 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;25:5877–83.
36. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of man and the cat during activation of the trigeminovascular system. Ann Neurol 1988;23:193–6.
37. 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.
38. Gupta S, Akerman S, van den Maagdenberg AM, Saxena PR, et al. Intravital microscopy on a closed cranial window in mice: a model to study trigeminovascular mechanisms involved in migraine. Cephalalgia 2006;26:1294–303.
39. Gupta S, Mehrotra S, Villalon CM, Perusquia M, et al. Potential role of female sex hormones in the pathophysiology of migraine. Pharmacol Ther 2007;113:321–40.
40. Hagner S, Stahl U, Knoblauch B, McGregor GP, et al. Calcitonin receptor-like receptor: identification and distribution in human peripheral tissues. Cell Tissue Res 2002;310:41–50.
41. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 2010;30:1179–86.
42. Hepp Z, Dodick DW, Varon SF, Gillard P, et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia 2015;35:478–88.
43. Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 2011;31:712–22.
44. Hewitt DJ, Martin V, Lipton RB, Brandes J, et al. Randomized controlled study of telcagepant plus ibuprofen or acetaminophen in migraine. Headache 2011;51:533–43.
45. Ho AP, Dahlof CG, Silberstein SD, Saper JR, et al. Randomized, controlled trial of telcagepant over four migraine attacks. Cephalalgia 2010;30:1443–57.
46. Ho TW, Connor KM, Zhang Y, Pearlman E, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 2014;83:958–66.
47. Ho TW, Ferrari MD, Dodick DW, Galet V, 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;372:2115–23.
48. Ho TW, Ho AP, Chaitman BR, Johnson C, et al. Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. Headache 2012;52:224–35.
49. Ho TW, Ho AP, Ge YJ, Assaid C, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine. Cephalalgia 2016;36:148–61.
50. Ho TW, Mannix LK, Fan X, Assaid C, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008;70:1304–12.
51. Holzer P. Peptidergic sensory neurons in the control of vascular functions: mechanisms and significance in the cutaneous and splanchnic vascular beds. Rev Physiol Biochem Pharmacol 1992;121:49–146.
52. Hostetler ED, Joshi AD, Sanabria-Bohorquez S, Fan H, et al. In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232. J Pharmacol Exp Ther 2013;347:478–86.
53. Hou Q, Barr T, Gee L, Vickers J, et al. Keratinocyte expression of calcitonin gene-related peptide beta: implications for neuropathic and inflammatory pain mechanisms. Pain 2011;152:2036–51.
54. Humphrey PPA, Feniuk W, Perren M, Oxford AW, et al. Sumatriptan succinate. Drugs Future 1989;14:35–9.
55. Itabashi A, Kashiwabara H, Shibuya M, Tanaka K, et al. The interaction of calcitonin gene-related peptide with angiotensin II on blood pressure and renin release. J Hypertens Suppl 1988;6:S418–20.
56. Jansen-Olesen I, Mortensen A, Edvinsson L. 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 1996;16:310–6.
57. Keller JT, Marfurt CF. Peptidergic and serotoninergic innervation of the rat dura mater. J Comp Neurol 1991;309:515–34.
58. Kendall MD, al-Shawaf AA. Innervation of the rat thymus gland. Brain Behav Immun 1991;5:9–28.
59. Kurosawa M, Messlinger K, Pawlak M, Schmidt RF. Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene-related peptide. Br J Pharmacol 1995;114:1397–402.
60. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, et al. CGRP may play a causative role in migraine. Cephalalgia 2002;22:54–61.
61. Lassen LH, Jacobsen VB, Haderslev PA, Sperling B, et al. Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients. J Headache Pain 2008;9:151–7.
62. Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, 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;507:1277–99.
63. Levy D, Burstein R, Kainz V, Jakubowski M, et al. Mast cell degranulation activates a pain pathway underlying migraine headache. Pain 2007;130:166–76.
64. Levy D, Burstein R, Strassman AM. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 2005;58:698–705.
65. 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.
66. Li YJ, Song QJ, Xiao J. Calcitonin gene-related peptide: an endogenous mediator of preconditioning. Acta Pharmacol Sin 2000;21:865–9.
67. Linscheid P, Seboek D, Schaer DJ, Zulewski H, et al. Expression and secretion of procalcitonin and calcitonin gene-related peptide by adherent monocytes and by macrophage-activated adipocytes. Crit Care Med 2004;32:1715–21.
68. Lundberg JM, Franco-Cereceda A, Alving K, Delay-Goyet P, et al. Release of calcitonin gene-related peptide from sensory neurons. Ann N Y Acad Sci 1992;657:187–93.
69. Ma W, Chabot JG, Powell KJ, Jhamandas K, et al. Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems. Neuroscience 2003;120:677–94.
70. Marcus R, Goadsby PJ, Dodick D, Stock D, et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 2014;34:114–25.
71. May A, Gijsman HJ, Wallnöfer A, Jones R, et al. Endothelin antagonist bosentan blocks neurogenic inflammation, but is not effective in aborting migraine attacks. Pain 1996;67:375–8.
72. McLatchie LM, Fraser NJ, Main MJ, Wise A, et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1998;393:333–9.
73. Messlinger K, Hanesch U, Baumgartel M, Trost B, et al. Innervation of the dura mater encephali of cat and rat: ultrastructure and calcitonin gene-related peptide-like and substance P-like immunoreactivity. Anat Embryol (Berl) 1993;188:219–37.
74. Mikami N, Matsushita H, Kato T, Kawasaki R, et al. Calcitonin gene-related peptide is an important regulator of cutaneous immunity: effect on dendritic cell and T cell functions. J Immunol 2011;186:6886–93.
75. Mizutani A, Okajima K, Murakami K, Mizutani S, et al. Activation of sensory neurons reduces ischemia/reperfusion-induced acute renal injury in rats. Anesthesiology 2009;110:361–9.
76. O‘Connor TP, van der Kooy D. Pattern of intracranial and extracranial projections of trigeminal ganglion cells. J Neurosci 1986;6:2200–7.
77. Olesen J, Diener HC, Husstedt IW, Goadsby PJ, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004;350:1104–10.
78. Pardridge WM, Kang YS, Buciak JL, Yang J. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate. Pharm Res 1995;12:807–16.
79. Penfield W, McNaughton FL. Dural headache and the innervation of the dura mater. Arch Neurol Psychiatry 1940;44:43–75.
80. Pozo-Rosich P, Storer RJ, Charbit AR, Goadsby PJ. Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. Cephalalgia 2015;35:1298–307.
81. Roon KI, Olesen J, Diener HC, Ellis P, et al. No acute antimigraine efficacy of CP-122,288, a highly potent inhibitor of neurogenic inflammation: results of two randomized, double-blind, placebo-controlled clinical trials. Ann Neurol 2000;47:238–41.
82. Saito K, Markowitz S, Moskowitz MA. Ergot alkaloids block neurogenic extravasation in dura mater: proposed action in vascular headaches. Ann Neurol 1988;24:732–7.
83. Schaible HG, Ebersberger A, Peppel P, Beck U, et al. Release of immunoreactive substance P in the trigeminal brain stem nuclear complex evoked by chemical stimulation of the nasal mucosa and the dura mater encephali – a study with antibody microprobes. Neuroscience 1997;76:273–84.
84. Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation–a 3T magnetic resonance angiography study. Brain 2008;131:2192–200.
85. Schwenger N, Dux M, de Col R, Carr R, et al. Interaction of calcitonin gene-related peptide, nitric oxide and histamine release in neurogenic blood flow and afferent activation in the rat cranial dura mater. Cephalalgia 2007;27:481–91.
86. Seiler K, Nusser JI, Lennerz JK, Neuhuber WL, et al. Changes in calcitonin gene-related peptide (CGRP) receptor component and nitric oxide receptor (sGC) immunoreactivity in rat trigeminal ganglion following glyceroltrinitrate pretreatment. J Headache Pain 2013;14:74.
87. Stankewitz A, Aderjan D, Eippert F, May A. Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. J Neurosci 2011;31:1937–43.
88. Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol 2004;142:1171–81.
89. Strassman AM, Weissner W, Williams M, Ali S, et al. Axon diameters and intradural trajectories of the dural innervation in the rat. J Comp Neurol 2004;473:364–76.
90. Sun H, Dodick DW, Silberstein S, Goadsby PJ, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016;15:382–90.
91. Tache Y. Brainstem neuropeptides and vagal protection of the gastric mucosal against injury: role of prostaglandins, nitric oxide and calcitonin-gene related peptide in capsaicin afferents. Curr Med Chem 2012;19:35–42.
92. Tfelt-Hansen PC, Koehler PJ. One hundred years of migraine research: major clinical and scientific observations from 1910 to 2010. Headache 2011;51:752–78.
93. Toda M, Suzuki T, Hosono K, Kurihara Y, et al. Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed Pharmacother 2008;62:352–9.
94. Ueda T, Ugawa S, Saishin Y, Shimada S. Expression of receptor-activity modifying protein (RAMP) mRNAs in the mouse brain. Brain Res Mol Brain Res 2001;93:36–45.
95. van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 1997;21:649–78.
96. Vause CV, Durham PL. Calcitonin gene-related peptide differentially regulates gene and protein expression in trigeminal glia cells: findings from array analysis. Neurosci Lett 2010;473:163–7.
97. Voss T, Lipton RB, Dodick DW, Dupre N, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 2016;36:887–98.
98. Walker CS, Eftekhari S, Bower RL, Wilderman A, et al. A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann Clin Transl Neurol 2015;2:595–608.
99. Wang H, Xing L, Li W, Hou L, et al. Production and secretion of calcitonin gene-related peptide from human lymphocytes. J Neuroimmunol 2002;130:155–62.
100. Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Cephalalgia 1997;17:518–24.
101. Wimalawansa SJ, Emson PC, MacIntyre I. Regional distribution of calcitonin gene-related peptide and its specific binding sites in rats with particular reference to the nervous system. Neuroendocrinology 1987;46:131–6.
102. Wimalawansa SJ, MacIntyre I. The presence of calcitonin gene-related peptide in human cerebrospinal fluid. Brain 1987;110:1647–55.
103. Xing LY, Xing YT, Tang YM, Guo JX, et al. Expression of calcitonin gene-related peptide (CGRP) mRNA in rat lymphocytes. Sheng Li Xue Bao 1998;50:423–30.
104. Xu G, Jiang D. The role and mechanism of exogenous calcitonin gene-related peptide on mesenchymal stem cell proliferation and osteogenetic formation. Cell Biochem Biophys 2014;69:369–78.
105. Zaidi M, Breimer LH, MacIntyre I. Biology of peptides from the calcitonin genes. Q J Exp Physiol 1987;72:371–408.
106. Zeller J, Poulsen KT, Sutton JE, Abdiche YN, et al. CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat. Br J Pharmacol 2008;155:1093–103.
107. Zhang JY, Yan GT, Liao J, Deng ZH, et al. Leptin attenuates cerebral ischemia/reperfusion injury partially by CGRP expression. Eur J Pharmacol 2011;671:61–9.
108. Zheng LR, Han J, Yao L, Sun YL, et al. Up-regulation of calcitonin gene-related peptide protects streptozotocin-induced diabetic hearts from ischemia/reperfusion injury. Int J Cardiol 2012;156:192–8.
109. Zlokovic BV, Skundric DS, Segal MB, Lipovac MN, et al. A saturable mechanism for transport of immunoglobulin G across the blood-brain barrier of the guinea pig. Exp Neurol 1990;107:263–70.
Prof. Dr.med. Karl Messlinger, Institut für Physiologie und Pathophysiologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen
Priv.-Doz. Dr.med. Dagny Holle-Lee, Prof. Dr.med. Hans-Christoph Diener, Westdeutsches Kopfschmerzzentrum und Neurologische Klinik der Universität Duisburg-Essen, Hufelandstr. 55, 45147 Essen, E-Mail: firstname.lastname@example.org