1932

Abstract

Migraine is a neurological disorder that manifests as a debilitating headache associated with altered sensory perception. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. Clinical trials carried out during the past decade have proved that CGRP receptor antagonists are effective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation. Despite this progress in the clinical arena, the mechanisms by which CGRP triggers migraine remain uncertain. This review discusses mechanisms whereby CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Future studies on epistatic and epigenetic regulators of CGRP actions are expected to shed further light on CGRP actions in migraine. In conclusion, targeting CGRP represents an approachable therapeutic strategy for migraine.

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2015-01-06
2024-04-16
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Literature Cited

  1. Goadsby PJ, Lipton RB, Ferrari MD. 1.  2002. Migraine—current understanding and treatment. N. Engl. J. Med. 346:257–70 [Google Scholar]
  2. Charles A. 2.  2013. The evolution of a migraine attack – a review of recent evidence. Headache 53:413–19 [Google Scholar]
  3. de Tommaso M, Ambrosini A, Brighina F, Coppola G, Perrotta A. 3.  et al. 2014. Altered processing of sensory stimuli in patients with migraine. Nat. Rev. Neurol. 10:144–55 [Google Scholar]
  4. 4. Headache Classif. Subcomm. Intl. Headache Society 2004. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24:Suppl. 19–160 [Google Scholar]
  5. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. 5.  2001. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41:646–57 [Google Scholar]
  6. Stewart WF, Wood C, Reed ML, Roy J, Lipton RB. 6. AMPP Advis. Group 2008. Cumulative lifetime migraine incidence in women and men. Cephalalgia 28:1170–78 [Google Scholar]
  7. Hawkins K, Wang S, Rupnow M. 7.  2008. Direct cost burden among insured US employees with migraine. Headache 48:553–63 [Google Scholar]
  8. Menken M, Munsat TL, Toole JF. 8.  2000. The Global Burden of Disease Study: implications for neurology. Arch. Neurol. 57:418–20 [Google Scholar]
  9. Loder E. 9.  2010. Triptan therapy in migraine. N. Engl. J. Med. 363:63–70 [Google Scholar]
  10. Diener HC, Lampl C, Reimnitz P, Voelker M. 10.  2006. Aspirin in the treatment of acute migraine attacks. Expert Rev. Neurother. 6:563–73 [Google Scholar]
  11. Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE. 11.  et al. 2010. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 30:804–14 [Google Scholar]
  12. Tfelt-Hansen P, Olesen J. 12.  2012. Taking the negative view of current migraine treatments: the unmet needs. CNS Drugs 26:375–82 [Google Scholar]
  13. Levy D, Burstein R. 13.  2011. The vascular theory of migraine: leave it or love it. Ann. Neurol. 69:600–1 [Google Scholar]
  14. Goadsby PJ. 14.  2009. The vascular theory of migraine—a great story wrecked by the facts. Brain 132:6–7 [Google Scholar]
  15. Brennan KC, Charles A. 15.  2010. An update on the blood vessel in migraine. Curr. Opin. Neurol. 23:266–74 [Google Scholar]
  16. Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Koning P. 16.  et al. 2011. Evidence for a vascular factor in migraine. Ann. Neurol. 69:635–45 [Google Scholar]
  17. Ashina M. 17.  2012. Vascular changes have a primary role in migraine. Cephalalgia 32:428–30 [Google Scholar]
  18. Charles A. 18.  2012. Migraine is not primarily a vascular disorder. Cephalalgia 32:431–32 [Google Scholar]
  19. Raddant AC, Russo AF. 19.  2011. Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev. Mol. Med. 13:e36 [Google Scholar]
  20. Messlinger K. 20.  2009. Migraine: Where and how does the pain originate. Exp. Brain Res. 196:179–93 [Google Scholar]
  21. Pietrobon D, Striessnig J. 21.  2003. Neurobiology of migraine. Nat. Rev. Neurosci. 4:386–98 [Google Scholar]
  22. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. 22.  2002. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 8:136–42 [Google Scholar]
  23. Lambert GA. 23.  2010. The lack of peripheral pathology in migraine headache. Headache 50:895–908 [Google Scholar]
  24. Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. 24.  2010. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 169:683–96 [Google Scholar]
  25. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. 25.  1982. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298:240–44 [Google Scholar]
  26. Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE. 26.  et al. 1983. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature 304:129–35 [Google Scholar]
  27. Russo AF, Dickerson IM. 27.  2006. CGRP: a multifunctional neuropeptide. Handbook of Neurochemistry and Molecular Neurobiology A Lajtha, R Lim 391–426 New York: Springer [Google Scholar]
  28. van Rossum D, Hanisch UK, Quirion R. 28.  1997. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci. Biobehav. Rev. 21:649–78 [Google Scholar]
  29. Recober A, Russo AF. 29.  2009. Calcitonin gene-related peptide: an update on the biology. Curr. Opin. Neurol. 22:241–46 [Google Scholar]
  30. Benarroch EE. 30.  2011. CGRP: sensory neuropeptide with multiple neurologic implications. Neurology 77:281–87 [Google Scholar]
  31. Kaiser EA, Russo AF. 31.  2013. CGRP and migraine: could PACAP play a role too. Neuropeptides 47:451–61 [Google Scholar]
  32. Breeze AL, Harvey TS, Bazzo R, Campbell ID. 32.  1991. Solution structure of human calcitonin gene-related peptide by 1H NMR and distance geometry with restrained molecular dynamics. Biochemistry 30:575–82 [Google Scholar]
  33. Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R. 33.  et al. 2002. International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol. Rev. 54:233–46 [Google Scholar]
  34. Amara SG, Arriza JL, Leff SE, Swanson LW, Evans RM, Rosenfeld MG. 34.  1985. Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide. Science 229:1094–97 [Google Scholar]
  35. Mulderry PK, Ghatei MA, Spokes RA, Jones PM, Pierson AM. 35.  et al. 1988. Differential expression of α-CGRP and β-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience 25:195–205 [Google Scholar]
  36. Russo AF, Nelson C, Roos BA, Rosenfeld MG. 36.  1988. Differential regulation of the coexpressed calcitonin/α-CGRP and β-CGRP neuroendocrine genes. J. Biol. Chem. 263:5–8 [Google Scholar]
  37. Sexton PM, Christopoulos G, Christopoulos A, Nylen ES, Snider RH Jr, Becker KL. 37.  2008. Procalcitonin has bioactivity at calcitonin receptor family complexes: potential mediator implications in sepsis. Crit. Care Med. 36:1637–40 [Google Scholar]
  38. Zhang Z, Dickerson IM, Russo AF. 38.  2006. Calcitonin gene-related peptide receptor activation by receptor activity-modifying protein-1 gene transfer to vascular smooth muscle cells. Endocrinology 147:1932–40 [Google Scholar]
  39. Zhang Z, Winborn CS, Marquez de Prado B, Russo AF. 39.  2007. Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J. Neurosci. 27:2693–703 [Google Scholar]
  40. Héroux M, Hogue M, Lemieux S, Bouvier M. 40.  2007. Functional calcitonin gene-related peptide receptors are formed by the asymmetric assembly of a calcitonin receptor-like receptor homo-oligomer and a monomer of receptor activity-modifying protein-1. J. Biol. Chem. 282:31610–20 [Google Scholar]
  41. Walker CS, Conner AC, Poyner DR, Hay DL. 41.  2010. Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol. Sci. 31:476–83 [Google Scholar]
  42. Archbold JK, Flanagan JU, Watkins HA, Gingell JJ, Hay DL. 42.  2011. Structural insights into RAMP modification of secretin family G protein-coupled receptors: implications for drug development. Trends Pharmacol. Sci. 32:591–600 [Google Scholar]
  43. ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT. 43.  et al. 2010. Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure 18:1083–93 [Google Scholar]
  44. Walker CS, Hay DL. 44.  2013. CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors. Br. J. Pharmacol. 170:1293–307 [Google Scholar]
  45. Petersen KA, Birk S, Kitamura K, Olesen J. 45.  2009. Effect of adrenomedullin on the cerebral circulation: relevance to primary headache disorders. Cephalalgia 29:23–30 [Google Scholar]
  46. Hay DL, Poyner DR, Quirion R. 46.  2008. International Union of Pharmacology. LXIX. Status of the calcitonin gene-related peptide subtype 2 receptor. Pharmacol. Rev. 60:143–45 [Google Scholar]
  47. Villalon CM, Olesen J. 47.  2009. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol. Ther. 124:309–23 [Google Scholar]
  48. Ho TW, Edvinsson L, Goadsby PJ. 48.  2010. CGRP and its receptors provide new insights into migraine pathophysiology. Nat. Rev. Neurol. 6:573–82 [Google Scholar]
  49. Goadsby PJ, Edvinsson L, Ekman R. 49.  1990. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28:183–87 [Google Scholar]
  50. Tfelt-Hansen P, Le H. 50.  2009. Calcitonin gene-related peptide in blood: Is it increased in the external jugular vein during migraine and cluster headache? A review. J. Headache Pain 10:137–43 [Google Scholar]
  51. Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J. 51.  2000. Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain 86:133–38 [Google Scholar]
  52. Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J. 52.  2013. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 81:1191–96 [Google Scholar]
  53. Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J. 53.  2005. No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann. Neurol. 58:561–68 [Google Scholar]
  54. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. 54.  2002. CGRP may play a causative role in migraine. Cephalalgia 22:54–61 [Google Scholar]
  55. Hansen JM, Hauge AW, Olesen J, Ashina M. 55.  2010. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30:1179–86 [Google Scholar]
  56. Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J. 56.  2005. BIBN4096BS antagonizes human α-calcitonin gene related peptide–induced headache and extracerebral artery dilatation. Clin. Pharmacol. Ther. 77:202–13 [Google Scholar]
  57. Recober A, Kuburas A, Zhang Z, Wemmie JA, Anderson MG, Russo AF. 57.  2009. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. J. Neurosci. 29:8798–804 [Google Scholar]
  58. Russo AF, Kuburas A, Kaiser EA, Raddant AC, Recober A. 58.  2009. A potential preclinical migraine model: CGRP-sensitized mice. Mol. Cell Pharmacol. 1:264–70 [Google Scholar]
  59. Schytz HW, Schoonman GG, Ashina M. 59.  2010. What have we learnt from triggering migraine. Curr. Opin. Neurol. 23:259–65 [Google Scholar]
  60. Edvinsson L. 60.  2008. CGRP blockers in migraine therapy: Where do they act. Br. J. Pharmacol. 155:967–69 [Google Scholar]
  61. Tfelt-Hansen P, Olesen J. 61.  2011. Possible site of action of CGRP antagonists in migraine. Cephalalgia 31:748–50 [Google Scholar]
  62. Fischer MJM, Koulchitsky S, Messlinger K. 62.  2005. 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. 25:5877–83 [Google Scholar]
  63. Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D. 63.  et al. 2004. Calcitonin gene–related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N. Engl. J. Med. 350:1104–10 [Google Scholar]
  64. Doods H, Arndt K, Rudolf K, Just S. 64.  2007. CGRP antagonists: unravelling the role of CGRP in migraine. Trends Pharmacol. Sci. 28:580–87 [Google Scholar]
  65. Bigal ME, Walter S, Rapoport AM. 65.  2013. Calcitonin gene-related peptide (CGRP) and migraine: current understanding and state of development. Headache 53:1230–44 [Google Scholar]
  66. Peroutka SJ. 66.  2014. Calcitonin gene-related peptide targeted immunotherapy for migraine: progress and challenges in treating headache. BioDrugs 28:237–44 [Google Scholar]
  67. Ho TW, Mannix LK, Fan X, Assaid C, Furtek C. 67.  et al. 2008. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70:1304–12 [Google Scholar]
  68. Kam-Hansen S, Jakubowski M, Kelley JM, Kirsch I, Hoaglin DC. 68.  et al. 2014. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci. Translational Med. 6:218ra5 [Google Scholar]
  69. Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J. 69.  et al. 2009. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 73:970–77 [Google Scholar]
  70. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J. 70.  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 372:2115–23 [Google Scholar]
  71. Connor KM, Aurora SK, Loeys T, Ashina M, Jones C. 71.  et al. 2011. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache 51:73–84 [Google Scholar]
  72. Cui XP, Ye JX, Lin H, Mu JS, Lin M. 72.  2013. Efficacy, safety, and tolerability of telcagepant in the treatment of acute migraine: a meta-analysis. Pain Pract. doi: 10.1111/papr.12158
  73. Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J. 73.  et al. 2014. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 83:958–66 [Google Scholar]
  74. Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ. 74.  et al. 2011. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 31:712–22 [Google Scholar]
  75. Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J. 75.  2011. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 31:573–84 [Google Scholar]
  76. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. 76.  2014. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34:114–25 [Google Scholar]
  77. Miranda LP, Shi L, Holder JR, Wright M, Gegg CV. 77.  et al. 2013. Peptide antagonists of the calcitonin gene-related peptide (CGRP) receptor with improved pharmacokinetics and pharmacodynamics. Biopolymers 100:422–30 [Google Scholar]
  78. Joshi P, Anderson C, Binch H, Hadida S, Yoo S. 78.  et al. 2014. Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 24:845–49 [Google Scholar]
  79. Goadsby P, Dodick D, Silberstein S, Lipton R, Olesen J. 79.  et al. 2014. Randomized, double-blind, placebo-controlled trial of ALD403, an anti-CGRP peptide antibody in the prevention of frequent episodic migraine. Presented at 66th Annu. Meet. Am. Acad. Neurol., April 26–May 3, Philadelphia, PA
  80. Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. 80.  2014. 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 13:885–92 [Google Scholar]
  81. Benschop RJ, Collins EC, Darling RJ, Allan BW, Leung D. 81.  et al. 2014. Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain. Osteoarthr. Cartil. 22:578–85 [Google Scholar]
  82. Bullock CM, Kelly S. 82.  2013. Calcitonin gene-related peptide receptor antagonists: beyond migraine pain—a possible analgesic strategy for osteoarthritis. Curr. Pain Headache Rep. 17:375 [Google Scholar]
  83. Bigal ME, Escandon R, Bronson M, Walter S, Sudworth M. 83.  et al. 2013. 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 34:483–92 [Google Scholar]
  84. Smillie SJ, King R, Kodji X, Outzen E, Pozsgai G. 84.  et al. 2014. An ongoing role of α-calcitonin gene-related peptide as part of a protective network against hypertension, vascular hypertrophy, and oxidative stress. Hypertension 63:1056–62 [Google Scholar]
  85. Woods IG, Schoppik D, Shi VJ, Zimmerman S, Coleman HA. 85.  et al. 2014. Neuropeptidergic signaling partitions arousal behaviors in zebrafish. J. Neurosci. 34:3142–60 [Google Scholar]
  86. Brain SD, Grant AD. 86.  2004. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol. Rev. 84:903–34 [Google Scholar]
  87. Olesen J, Burstein R, Ashina M, Tfelt-Hansen P. 87.  2009. Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol. 8:679–90 [Google Scholar]
  88. Levy D, Burstein R, Kainz V, Jakubowski M, Strassman AM. 88.  2007. Mast cell degranulation activates a pain pathway underlying migraine headache. Pain 130:166–76 [Google Scholar]
  89. Strassman AM, Raymond SA, Burstein R. 89.  1996. Sensitization of meningeal sensory neurons and the origin of headaches. Nature 384:560–64 [Google Scholar]
  90. Bernstein C, Burstein R. 90.  2012. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J. Clin. Neurol. 8:89–99 [Google Scholar]
  91. Ottosson A, Edvinsson L. 91.  1997. Release of histamine from dural mast cells by substance P and calcitonin gene-related peptide. Cephalalgia 17:166–74 [Google Scholar]
  92. Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A. 92.  2005. The role of mast cells in migraine pathophysiology. Brain Res. Rev. 49:65–76 [Google Scholar]
  93. Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW. 93.  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. 507:1277–99 [Google Scholar]
  94. Eftekhari S1, Warfvinge K, Blixt FW, Edvinsson L. 94.  2013. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J. Pain 14:1289–303 [Google Scholar]
  95. Thalakoti S, Patil VV, Damodaram S, Vause CV, Langford LE. 95.  et al. 2007. Neuron-glia signaling in trigeminal ganglion: implications for migraine pathology. Headache 47:1008–23 discussion 24–25 [Google Scholar]
  96. Capuano A, De Corato A, Lisi L, Tringali G, Navarra P, Dello Russo C. 96.  2009. Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Mol. Pain 5:43 [Google Scholar]
  97. De Corato A, Lisi L, Capuano A, Tringali G, Tramutola A. 97.  et al. 2011. Trigeminal satellite cells express functional calcitonin gene-related peptide receptors, whose activation enhances interleukin-1β pro-inflammatory effects. J. Neuroimmunol. 237:39–46 [Google Scholar]
  98. Diener HC. 98.  2003. RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia 23:183–85 [Google Scholar]
  99. Levy D, Burstein R, Strassman AM. 99.  2005. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann. Neurol. 58:698–705 [Google Scholar]
  100. Sixt ML, Messlinger K, Fischer MJM. 100.  2009. Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus. Brain 132:3134–41 [Google Scholar]
  101. Storer RJ, Akerman S, Goadsby PJ. 101.  2004. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br. J. Pharmacol. 142:1171–81 [Google Scholar]
  102. Giniatullin R, Nistri A, Fabbretti E. 102.  2008. Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol. Neurobiol. 37:83–90 [Google Scholar]
  103. Simonetti M, Giniatullin R, Fabbretti E. 103.  2008. Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. J. Biol. Chem. 283:18743–52 [Google Scholar]
  104. Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L. 104.  et al. 2000. Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407:1015–17 [Google Scholar]
  105. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M. 105.  et al. 2005. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–21 [Google Scholar]
  106. Fischer M, Wille G, Klien S, Shanib H, Holle D. 106.  et al. 2012. Brain-derived neurotrophic factor in primary headaches. J. Headache Pain 13:469–75 [Google Scholar]
  107. Bowen EJ, Schmidt TW, Firm CS, Russo AF, Durham PL. 107.  2006. Tumor necrosis factor-α stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons. J. Neurochem. 96:65–77 [Google Scholar]
  108. Tajti J, Uddman R, Moller S, Sundler F, Edvinsson L. 108.  1999. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J. Auton. Nerv. Syst. 76:176–83 [Google Scholar]
  109. Edvinsson L, Eftekhari S, Salvatore CA, Warfvinge K. 109.  2011. Cerebellar distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) in rat. Mol. Cell. Neurosci. 46:333–39 [Google Scholar]
  110. Seiler K, Nusser JI, Lennerz JK, Neuhuber WL, Messlinger K. 110.  2013. 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 14:74 [Google Scholar]
  111. Hay DL, Poyner DR, Sexton PM. 111.  2006. GPCR modulation by RAMPs. Pharmacol. Ther. 109:173–97 [Google Scholar]
  112. Russo AF, Recober A. 112.  2013. Unanswered questions in headache: So what is photophobia, anyway. Headache 53:1677–78 [Google Scholar]
  113. Noseda R, Burstein R. 113.  2011. Advances in understanding the mechanisms of migraine-type photophobia. Curr. Opin. Neurol. 24:197–202 [Google Scholar]
  114. Digre KB, Brennan KC. 114.  2012. Shedding light on photophobia. J. Neuroophthalmol. 32:68–81 [Google Scholar]
  115. Recober A, Kaiser EA, Kuburas A, Russo AF. 115.  2010. Induction of multiple photophobic behaviors in a transgenic mouse sensitized to CGRP. Neuropharmacology 58:156–65 [Google Scholar]
  116. Kaiser EA, Kuburas A, Recober A, Russo AF. 116.  2012. Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT1B/D agonist. J. Neurosci. 32:15439–49 [Google Scholar]
  117. Rossi HL, Recober A. 117.  2014. Photophobia in primary headaches. Headache. In press
  118. Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB. 118.  et al. 2010. A neural mechanism for exacerbation of headache by light. Nat. Neurosci. 13:239–45 [Google Scholar]
  119. Maleki N, Becerra L, Upadhyay J, Burstein R, Borsook D. 119.  2012. Direct optic nerve pulvinar connections defined by diffusion MR tractography in humans: implications for photophobia. Hum. Brain Mapp. 33:75–88 [Google Scholar]
  120. Summ O, Charbit AR, Andreou AP, Goadsby PJ. 120.  2010. Modulation of nocioceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus. Brain 133:2540–48 [Google Scholar]
  121. Noseda R, Kainz V, Borsook D, Burstein R. 121.  2014. Neurochemical pathways that converge on thalamic trigeminovascular neurons: potential substrate for modulation of migraine by sleep, food intake, stress and anxiety. PLOS ONE 9:e103929 [Google Scholar]
  122. Marvizón JCG, Pérez OA, Song B, Chen W, Bunnett NW. 122.  et al. 2007. Calcitonin receptor-like receptor and receptor activity modifying protein 1 in the rat dorsal horn: localization in glutamatergic presynaptic terminals containing opioids and adrenergic α2C receptors. Neuroscience 148:250–65 [Google Scholar]
  123. Seybold VS. 123.  2009. The role of peptides in central sensitization. Handb. Exp. Pharmacol. 194:451–91 [Google Scholar]
  124. Fischer MJM. 124.  2010. Calcitonin gene-related peptide receptor antagonists for migraine. Expert Opin. Investig. Drugs 19:815–23 [Google Scholar]
  125. Gu XL, Yu LC. 125.  2007. The colocalization of CGRP receptor and AMPA receptor in the spinal dorsal horn neuron of rat: a morphological and electrophysiological study. Neurosci. Lett. 414:237–41 [Google Scholar]
  126. Marquez de Prado B, Hammond DL, Russo AF. 126.  2009. Genetic enhancement of calcitonin gene-related peptide-induced central sensitization to mechanical stimuli in mice. J. Pain 10:992–1000 [Google Scholar]
  127. Rogoz K, Andersen HH, Kullander K, Lagerstrom MC. 127.  2014. Glutamate, substance P, and calcitonin gene-related peptide cooperate in inflammation-induced heat hyperalgesia. Mol. Pharmacol. 85:322–34 [Google Scholar]
  128. Sun RQ, Tu YJ, Lawand NB, Yan JY, Lin Q, Willis WD. 128.  2004. Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization. J. Neurophysiol. 92:2859–66 [Google Scholar]
  129. Sink KS, Walker DL, Yang Y, Davis M. 129.  2011. Calcitonin gene-related peptide in the bed nucleus of the stria terminalis produces an anxiety-like pattern of behavior and increases neural activation in anxiety-related structures. J. Neurosci. 31:1802–10 [Google Scholar]
  130. Neugebauer V, Li W, Bird GC, Han JS. 130.  2004. The amygdala and persistent pain. Neuroscientist 10:221–34 [Google Scholar]
  131. Han JS, Adwanikar H, Li Z, Ji G, Neugebauer V. 131.  2010. Facilitation of synaptic transmission and pain responses by CGRP in the amygdala of normal rats. Mol. Pain 6:10 [Google Scholar]
  132. Huang Y, Brodda-Jansen G, Lundeberg T, Yu LC. 132.  2000. Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone. Brain Res. 873:54–59 [Google Scholar]
  133. Charbit AR, Akerman S, Holland PR, Goadsby PJ. 133.  2009. 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. 29:12532–41 [Google Scholar]
  134. Charles AC, Baca SM. 134.  2013. Cortical spreading depression and migraine. Nat. Rev. Neurol. 9:637–44 [Google Scholar]
  135. Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R. 135.  2010. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J. Neurosci. 30:8807–14 [Google Scholar]
  136. Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. 136.  2011. Activation of central trigeminovascular neurons by cortical spreading depression. Ann. Neurol. 69:855–65 [Google Scholar]
  137. Levy D. 137.  2010. Migraine pain and nociceptor activation—where do we stand. Headache 50:909–16 [Google Scholar]
  138. Kosaras B, Jakubowski M, Kainz V, Burstein R. 138.  2009. Sensory innervation of the calvarial bones of the mouse. J. Comp. Neurol. 515:331–48 [Google Scholar]
  139. Reuter U, Weber JR, Gold L, Arnold G, Wolf T. 139.  et al. 1998. Perivascular nerves contribute to cortical spreading depression-associated hyperemia in rats. Am. J. Physiol. 274:H1979–87 [Google Scholar]
  140. Colonna DM, Meng W, Deal DD, Busija DW. 140.  1994. Calcitonin gene-related peptide promotes cerebrovascular dilation during cortical spreading depression in rabbits. Am. J. Physiol. 266:H1095–102 [Google Scholar]
  141. Wahl M, Schilling L, Parsons AA, Kaumann A. 141.  1994. Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression. Brain Res. 637:204–10 [Google Scholar]
  142. Tozzi A, de Iure A, Di Filippo M, Costa C, Caproni S. 142.  et al. 2012. Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc. Natl. Acad. Sci. USA 109:18985–90 [Google Scholar]
  143. Viggiano A, Viggiano E, Valentino I, Monda M, Viggiano A, De Luca B. 143.  2011. Cortical spreading depression affects reactive oxygen species production. Brain Res. 1368:11–18 [Google Scholar]
  144. Shatillo A, Koroleva K, Giniatullina R, Naumenko N, Slastnikova AA. 144.  et al. 2013. Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system. Neuroscience 253:341–49 [Google Scholar]
  145. Raddant AC, Russo AF. 145.  2014. Reactive oxygen species induce procalcitonin expression in trigeminal ganglia glia. Headache 54:472–84 [Google Scholar]
  146. Park KY, Fletcher JR, Raddant AC, Russo AF. 146.  2011. Epigenetic regulation of the calcitonin gene-related peptide gene in trigeminal glia. Cephalalgia 31:614–24 [Google Scholar]
  147. Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F. 147.  et al. 2013. Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat. Genet. 45:912–17 [Google Scholar]
  148. Esserlind AL, Christensen AF, Le H, Kirchmann M, Hauge AW. 148.  et al. 2013. Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine. Eur. J. Neurol. 20:765–72 [Google Scholar]
  149. Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC. 149.  et al. 2013. Casein kinase Iδ mutations in familial migraine and advanced sleep phase. Sci. Translational Med. 5:183ra56 [Google Scholar]
  150. Eising E, de Vries B, Ferrari MD, Terwindt GM, van den Maagdenberg AMJM. 150.  2013. Pearls and pitfalls in genetic studies of migraine. Cephalalgia 33:614–25 [Google Scholar]
  151. Menon S, Buteri J, Roy B, Murrell M, Quinlan S. 151.  et al. 2011. Association study of calcitonin gene-related polypeptide-alpha (CALCA) gene polymorphism with migraine. Brain Res. 1378:119–24 [Google Scholar]
  152. Jansen-Olesen I, Baun M, Amrutkar DV, Ramachandran R, Christophersen DV, Olesen J. 152.  2014. PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides 48:53–64 [Google Scholar]
  153. Eising E, Datson NA, van den Maagdenberg AMJM, Ferrari MD. 153.  2013. Epigenetic mechanisms in migraine: a promising avenue?. BMC Med. 11:26 [Google Scholar]
  154. Cutrer FM, Limmroth V, Moskowitz MA. 154.  1997. Possible mechanisms of valproate in migraine prophylaxis. Cephalalgia 17:93–100 [Google Scholar]
  155. Nalivaeva NN, Belyaev ND, Turner AJ. 155.  2009. Sodium valproate: an old drug with new roles. Trends Pharmacol. Sci. 30:509–14 [Google Scholar]
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