Discovery techniques for calcitonin gene-related peptide receptor antagonists for potential antimigraine therapies

Expert Opinion on Drug Discovery

Volumn 8, Issue 11, 2013, Pages 1309-1323

  Labruijere, Sieneke ^a   Ibrahimi, Khatera ^a   Chan, Kayi Y ^a   Van Den Brink, Antoinette Maassen ^a  

^a ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

CGRP; CGRP receptor antagonist; Experimental models; Migraine; Telcagepant

Indexed keywords

ANTIBODY; ANTIMIGRAINE AGENT; BI 44370 TA; CALCITONIN GENE RELATED PEPTIDE; CALCITONIN GENE RELATED PEPTIDE RECEPTOR; CALCITONIN GENE RELATED PEPTIDE RECEPTOR ANTAGONIST; CALCITONIN LIKE RECEPTOR; CAPSAICIN; ERGOT ALKALOID; GLYCEROL NITRATE; HYPOPHYSIS ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE; LY 2951742; MK 3207; OLCEGEPANT; PROSTAGLANDIN E2; PROTEIN FOS; RECEPTOR ACTIVITY MODIFYING PROTEIN 1; RECEPTOR COMPONENT PROTEIN; RIMEGEPANT; RIZATRIPTAN; SUMATRIPTAN; TELCAGEPANT; TRIPTAN DERIVATIVE; UNCLASSIFIED DRUG; VASOACTIVE INTESTINAL POLYPEPTIDE;

BLOOD BRAIN BARRIER; BRAIN ANGIOGRAPHY; BRAIN BLOOD FLOW; BRAIN BLOOD VESSEL; BRAIN BLOOD VOLUME; BRAIN ELECTROPHYSIOLOGY; BRAIN SLICE; CARDIOVASCULAR SYSTEM; CENTRAL NERVOUS SYSTEM; CEREBROSPINAL FLUID LEVEL; CONSTIPATION; DIZZINESS; DRUG BIOAVAILABILITY; DRUG DOSE COMPARISON; DRUG DOSE REDUCTION; DRUG EFFECT; DRUG EFFICACY; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; ELECTROSTIMULATION; EXPERIMENTAL MODEL; FATIGUE; FUNCTIONAL MAGNETIC RESONANCE IMAGING; HEADACHE; HUMAN; HYPERTRANSAMINASEMIA; IN VITRO STUDY; IN VIVO STUDY; INFUSION; INTRAVITAL MICROSCOPY; LASER DOPPLER FLOWMETRY; MAGNETIC RESONANCE ANGIOGRAPHY; MICROSCOPY; MIGRAINE; NAUSEA; NEUROPHARMACOLOGY; NOCICEPTION; NONHUMAN; PARESTHESIA; PATHOPHYSIOLOGY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SINGLE DRUG DOSE; SKIN BLOOD FLOW; SOMNOLENCE; TRANSGENIC MOUSE; TREATMENT OUTCOME; TRIGEMINUS GANGLION; UNSPECIFIED SIDE EFFECT; VASODILATATION; VOMITING; XEROSTOMIA;

ANALGESICS; ANIMALS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; DRUG DISCOVERY; HUMANS; MIGRAINE DISORDERS; RECEPTORS, CALCITONIN GENE-RELATED PEPTIDE;

EID: 84886619745     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2013.826644     Document Type: Review

References (127)

1. Olesen J, Steiner TJ. The International classification of headache disorders, 2nd edn (ICDH-II). J Neurol Neurosurg Psychiatry 2004;75: 808-11
2. Kelman L. The aura: a tertiary care study of 952 migraine patients. Cephalalgia 2004;24: 728-34
3. Charles A. The evolution of a migraine attack - a review of recent evidence. Headache 2013;53: 413-19
4. Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27: 193-210
5. Goadsby PJ. Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med 2007;13: 39-44
6. Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalalgia 2002;22: 491-512
7. Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache 2003;43: 144-66
8. MaassenVanDenBrink A, Reekers M, Bax WA, et al. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 1998;98: 25-30
9. Edvinsson L, Villalón CM, MaassenVanDenBrink A. Basic mechanisms of migraine and its acute treatment. Pharmacol Ther 2012;136: 319-33 .. A recent review on the pathophysiological mechanisms of migraine with a special focus on CGRP.
10. Gupta S, Villalón CM. The relevance of preclinical research models for the development of antimigraine drugs: focus on 5-HT(1B/1D) and CGRP receptors. Pharmacol Ther 2010;128: 170-90
11. 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 .. A seminal paper describing an increae in plasma levels of CGRP during migraine.
12. Zagami AS, Goadsby PJ, Edvinsson L. Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides 1990;16: 69-75
13. Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Ther Adv Neurol Disord 2010;3: 369-78
14. Wimalawansa SJ. Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev 1996;17: 533-85
15. Edvinsson L, Ho TW. CGRP receptor antagonism and migraine. Neurotherapeutics 2010;7: 164-75
16. Walker CS, Conner AC, Poyner DR, et al. Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol Sci 2010;31: 476-83
17. Durham PL. CGRP-receptor antagonists-a fresh approach to migraine therapy? N Engl J Med 2004;350: 1073-5
18. Villalón CM, Centurión D, Valdivia LF, et al. Migraine: pathophysiology, pharmacology, treatment and future trends. Curr Vasc Pharmacol 2003;1: 71-84
19. Iovino M, Feifel U, Yong CL, et al. Safety, tolerability and pharmacokinetics of BIBN 4096 BS, the first selective small molecule calcitonin gene-related peptide receptor antagonist, following single intravenous administration in healthy volunteers. Cephalalgia 2004;24: 645-56
20. Salvatore CA, Hershey JC, Corcoran HA, et al. 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-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J Pharmacol Exp Ther 2008;324: 416-21
21. Salvatore CA, Moore EL, Calamari A, et al. Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist. J Pharmacol Exp Ther 2010;333: 152-60
22. 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: 139-47
23. Olesen J, Diener HC, Husstedt IW, 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 .. First clinical trial on olcegepant after intravenous administration.
24. Ho TW, Mannix LK, Fan X, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008;70: 1304-12 .. Clinical trial on the efficacy of telcagepant after oral administration.
25. 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: 2115-23
26. Connor KM, Shapiro RE, Diener HC, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 2009;73: 970-7
27. 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;50: 1367-76
28. Hewitt DJ, Aurora SK, Dodick DW, et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 2011;31: 712-22
29. Diener HC, Barbanti P, Dahlof C, et al. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 2011;31: 573-84
30. Tong G, Savant I, Jariwala N, et al. Phase I single and multiple dose study to evaluate the safety, tolerability, and pharmacokinetics of BMS-927711 in healthy subjects. J Headache Pain 2013;1:P118
31. Chan KY, Edvinsson L, Eftekhari S, et al. Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries. J Pharmacol Exp Ther 2010;334: 746-52
32. Moreno MJ, Abounader R, Hebert E, et al. Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment. Neuropharmacology 2002;42: 568-76
33. Gupta S, Lozano-Cuenca J, Villalón CM, et al. Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries. Naunyn Schmiedebergs Arch Pharmacol 2007;375: 29-38
34. Edvinsson L, Chan KY, Eftekhari S, et al. Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries. Cephalalgia 2010;30: 1233-40 .. A paper on the pharmacological characterization of telcagepant in human isolated cranial arteries.
35. Shahid M, Buys ES. Assessing murine resistance artery function using pressure myography. J Vis Exp; 2013;76
36. 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
37. Marichal-Cancino BA, Gonzalez-Hernandez A, Manrique-Maldonado G, et al. Intrathecal dihydroergotamine inhibits capsaicin-induced vasodilatation in the canine external carotid circulation via GR127935- and rauwolscine-sensitive receptors. Eur J Pharmacol 2012;692: 69-77
38. Gonzalez-Hernandez A, Manrique-Maldonado G, Lozano-Cuenca J, et al. The 5-HT(1) receptors inhibiting the rat vasodepressor sensory CGRPergic outflow: further involvement of 5-HT(1F), but not 5-HT (1A) or 5-HT(1D), subtypes. Eur J Pharmacol 2011;659: 233-43
39. Edvinsson L, Linde M. New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet 2010;376: 645-55
40. Williamson DJ, Hargreaves RJ, Hill RG, et al. Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat- intravital microscope studies. Cephalalgia 1997;17: 525-31
41. Gupta S, Akerman S, van den Maagdenberg AM, 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
42. Williamson DJ, Hargreaves RJ, Hill RG, et al. 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
43. Akerman S, Williamson DJ, Kaube H, et al. Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. Br J Pharmacol 2002;137: 62-8
44. Akerman S, Goadsby PJ. Topiramate inhibits trigeminovascular activation: an intravital microscopy study. Br J Pharmacol 2005;146: 7-14
45. Akerman S, Williamson DJ, Goadsby PJ. Voltage-dependent calcium channels are involved in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism. Br J Pharmacol 2003;140: 558-66
46. Chan KY, Gupta S, de Vries R, et al. Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model. Br J Pharmacol 2010;160: 1316-25
47. Okazawa H, Tsuchida T, Pagani M, et al. Effects of 5-HT1B/1D receptor agonist rizatriptan on cerebral blood flow and blood volume in normal circulation. J Cereb Blood Flow Metab 2006;26: 92-8
48. Sakai Y, Dobson C, Diksic M, et al. Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology 2008;70: 431-9
49. Vermeersch S, de Hoon J, De Saint-Hubert B, et al. PET imaging in healthy subjects and migraineurs suggests CGRP receptor antagonists do not have to act centrally to achieve clinical efficacy. J Headache Pain 2013;1:P224
50. Bandettini PA. Seven topics in functional magnetic resonance imaging. J Integr Neurosci 2009;8: 371-403
51. Ogawa S, Lee TM, Kay AR, et al. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci USA 1990;87: 9868-72
52. Asghar MS, Hansen AE, Larsson HB, et al. Effect of CGRP and sumatriptan on the BOLD response in visual cortex. J Headache Pain 2012;13: 159-66
53. Asghar MS, Hansen AE, Kapijimpanga T, et al. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology 2010;75: 1520-6
54. Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389: 816-24
55. Van der Schueren BJ, de Hoon JN, Vanmolkot FH, et al. Reproducibility of the capsaicin-induced dermal blood flow response as assessed by laser Doppler perfusion imaging. Br J Clin Pharmacol 2007;64: 580-90
56. Sinclair SR, Kane SA, Van der Schueren BJ, et al. Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974). Br J Clin Pharmacol 2010;69: 15-22
57. Buzzi MG, Carter WB, Shimizu T, et al. 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
58. Durand S, Fromy B, Bouye P, et al. Current-induced vasodilation during water iontophoresis (5 min, 0.10 mA) is delayed from current onset and involves aspirin sensitive mechanisms. J Vasc Res 2002;39: 59-71
59. Ibrahimi K, Danser A, Villalon C, et al. Influence of varying estrogen levels on trigeminal CGRP release in healthy women. J Headache Pain 2013;1:P123
60. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(Suppl 7): 1-96
61. Hansen JM, Hauge AW, Olesen J, et al. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 2010;30: 1179-86
62. Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia 2002;22: 54-61
63. Thomsen LL, Kruuse C, Iversen HK, et al. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1994;1: 73-80
64. Christiansen I, Thomsen LL, Daugaard D, et al. Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia 1999;19: 660-7; discussion 26
65. Hoivik HO, Laurijssens BE, Harnisch LO, et al. Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. Cephalalgia 2010;30: 1458-67
66. Tvedskov JF, Tfelt-Hansen P, Petersen KA, et al. CGRP receptor antagonist olcegepant (BIBN4096BS) does not prevent glyceryl trinitrate-induced migraine. Cephalalgia 2010;30: 1346-53
67. Schytz HW, Birk S, Wienecke T, et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 2009;132: 16-25
68. Rahmann A, Wienecke T, Hansen JM, et al. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 2008;28: 226-36
69. Harmar AJ, Arimura A, Gozes I, et al. International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev 1998;50: 265-70
70. 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: 310-16
71. Emery AC, Eiden LE. Signaling through the neuropeptide GPCR PAC(1) induces neuritogenesis via a single linear cAMPand ERK-dependent pathway using a novel cAMP sensor. FASEB J 2012;26: 3199-211
72. Wienecke T, Olesen J, Oturai PS, et al. Prostaglandin E2(PGE2) induces headache in healthy subjects. Cephalalgia 2009;29: 509-19
73. Antonova M, Wienecke T, Olesen J, et al. Prostaglandin E(2) induces immediate migraine-like attack in migraine patients without aura. Cephalalgia 2012;32: 822-33
74. Hunt SP, Pini A, Evan G. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature 1987;328: 632-4
75. Mitsikostas DD, Sanchez del Rio M. Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev 2001;35: 20-35
76. Andreou AP, Summ O, Charbit AR, et al. Animal models of headache: from bedside to bench and back to bedside. Expert Rev Neurother 2010;10: 389-411
77. Clayton JS, Gaskin PJ, Beattie DT. Attenuation of Fos-like immunoreactivity in the trigeminal nucleus caudalis following trigeminovascular activation in the anaesthetised guinea-pig. Brain Res 1997;775: 74-80
78. Bohar Z, Fejes-Szabo A, Tar L, et al. Evaluation of c-Fos immunoreactivity in the rat brainstem nuclei relevant in migraine pathogenesis after electrical stimulation of the trigeminal ganglion. Neurol Sci 2013; Epub ahead of print
79. Mitsikostas DD, Sanchez del Rio M, Waeber C, et al. The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. Pain 1998;76: 239-48
80. Strassman AM, Potrebic S, Maciewicz RJ. Anatomical properties of brainstem trigeminal neurons that respond to electrical stimulation of dural blood vessels. J Comp Neurol 1994;346: 349-65
81. Kaube H, Keay KA, Hoskin KL, et al. 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 1993;629: 95-102
82. Goadsby PJ, Hoskin KL. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J Anat 1997;190(Pt 3): 367-75
83. Hoskin KL, Bulmer DC, Goadsby PJ. Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus is reduced by L-NAME. Neurosci Lett 1999;266: 173-6
84. Edvinsson L, Goadsby PJ. Neuropeptides in migraine and cluster headache. Cephalalgia 1994;14: 320-7
85. Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res 1995;682: 167-81
86. Offenhauser N, Zinck T, Hoffmann J, et al. CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia 2005;25: 225-36
87. Chatchaisak D, Srikiatkhachorn A, Maneesri-le Grand S, et al. The role of calcitonin gene-related peptide on the increase in transient receptor potential vanilloid-1 levels in trigeminal ganglion and trigeminal nucleus caudalis activation of rat. J Chem Neuroanat 2013;47: 50-6
88. Sixt ML, Messlinger K, Fischer MJ. Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus. Brain 2009;132: 3134-41
89. Bullitt E, Lee CL, Light AR, et al. The effect of stimulus duration on noxious-stimulus induced c-fos expression in the rodent spinal cord. Brain Res 1992;580: 172-9
90. Bergerot A, Holland PR, Akerman S, et al. Animal models of migraine: looking at the component parts of a complex disorder. Eur J Neurosci 2006;24: 1517-34
91. Koulchitsky S, Fischer MJ, Messlinger K. Calcitonin gene-related peptide receptor inhibition reduces neuronal activity induced by prolonged increase in nitric oxide in the rat spinal trigeminal nucleus. Cephalalgia 2009;29: 408-17
92. Storer RJ, Goadsby PJ. Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat. Brain 1997;120(Pt 12): 2171-7
93. Shields KG, Storer RJ, Akerman S, et al. Calcium channels modulate nociceptive transmission in the trigeminal nucleus of the cat. Neuroscience 2005;135: 203-12
94. Bahra A, Matharu MS, Buchel C, et al. Brainstem activation specific to migraine headache. Lancet 2001;357: 1016-17
95. DaSilva AF, Becerra L, Makris N, et al. Somatotopic activation in the human trigeminal pain pathway. J Neurosci 2002;22: 8183-92
96. Kobari M, Meyer JS, Ichijo M, et al. Hyperperfusion of cerebral cortex, thalamus and basal ganglia during spontaneously occurring migraine headaches. Headache 1989;29: 282-9
97. Percheron G. Thalamus. In: Paxinos G, May J, editors. The human nervous system. Elsevier; Amsterdam: 2003. p. 592-675
98. Shields KG, Goadsby PJ. Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target? Neurobiol Dis 2006;23: 491-501
99. Shields KG, Goadsby PJ. Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine? Brain 2005;128: 86-97
100. Andreou AP, Shields KG, Goadsby PJ. GABA and valproate modulate trigeminovascular nociceptive transmission in the thalamus. Neurobiol Dis 2010;37: 314-23
101. Summ O, Charbit AR, Andreou AP, et al. Modulation of nocioceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus. Brain 2010;133: 2540-8
102. 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
103. Recober A, Kuburas A, Zhang Z, et al. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. J Neurosci 2009;29: 8798-804
104. Zhang L, Hoff AO, Wimalawansa SJ, et al. Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity. Pain 2001;89: 265-73
105. Gangula PR, Zhao H, Supowit SC, et al. Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice. Hypertension 2000;35: 470-5
106. Barbanti P, Aurilia C, Egeo G, et al. Future trends in drugs for migraine prophylaxis. Neurol Sci 2012;33(Suppl 1):S137-40
107. Zhu D, Zhang J, Zhou L, et al. A human CGRP receptor antagonist antibody, AA95, is effective in inhibiting capsaicin-induced increase in dermal blood flow in cynomolgus monkeys. Abstract of 54th Annual Scientific Meeting of the American Headache Society. Headache 2012;52: 862-914
108. Chai W, Mehrotra S, Jan Danser AH, et al. The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts. Eur J Pharmacol 2006;531: 246-53
109. Li D, Li NS, Chen QQ, et al. Calcitonin gene-related peptide-mediated cardioprotection of postconditioning in isolated rat hearts. Regul Pept 2008;147: 4-8
110. Li YJ, Peng J. The cardioprotection of calcitonin gene-related peptide-mediated preconditioning. Eur J Pharmacol 2002;442: 173-7
111. Song S, Liu N, Liu W, et al. The effect of pretreatment with calcitonin gene-related peptide on attenuation of liver ischemia and reperfusion injury due to oxygen free radicals and apoptosis. Hepatogastroenterology 2009;56: 1724-9
112. Schebesch KM, Herbst A, Bele S, et al. Calcitonin-gene related peptide and cerebral vasospasm. J Clin Neurosci 2013;20: 584-6
113. Wang L, Wang DH. TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation 2005;112: 3617-23
114. Kallner G, Gonon A, Franco-Cereceda A. Calcitonin gene-related peptide in myocardial ischaemia and reperfusion in the pig. Cardiovasc Res 1998;38: 493-9
115. Wu DM, van Zwieten PA, Doods HN. Effects of calcitonin gene-related peptide and BIBN4096BS on myocardial ischemia in anesthetized rats. Acta Pharmacol Sin 2001;22: 588-94
116. Zeller J, Poulsen KT, Sutton JE, 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
117. Valentini A, Petraglia F, De Vita D, et al. Changes of plasma calcitonin gene-related peptide levels in postmenopausal women. Am J Obstet Gynecol 1996;175: 638-42
118. Gennari C, Nami R, Pecchi S, et al. Plethysmographic evaluation of the vascular effects of human calcitonin gene-related peptide in man. Angiology 1991;42: 462-7
119. Hay DL, Poyner DR. Calcitonin gene-related peptide, adrenomedullin and flushing. Maturitas 2009;64: 104-8
120. MacGregor EA. Migraine, the menopause and hormone replacement therapy: a clinical review. J Fam Plann Reprod Health Care 2007;33: 245-9
121. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012;19: 257-71
122. Nappi RE, Cagnacci A, Granella F, et al. Course of primary headaches during hormone replacement therapy. Maturitas 2001;38: 157-63
123. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288: 321-33
124. Evers S, Afra J, Frese A, et al. EFNS guideline on the drug treatment of migraine-revised report of an EFNS task force. Eur J Neurol 2009;16: 968-81
125. Ho TW, Olesen J, Dodick DW, et al. Antimigraine efficacy of telcagepant based on patient's historical triptan response. Headache 2011;51: 64-72
126. Amin FM, Asghar MS, Hougaard A, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol 2013;12: 454-61
127. Zhang Z, Winborn CS, Marquez de Prado B, et al. Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci 2007;27: 2693-703