Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

CGRP and its receptors provide new insights into migraine pathophysiology

Abstract

Over the past 300 years, the migraine field has been dominated by two main theories—the vascular theory and the central neuronal theory. The success of vasoconstrictors such as ergotamine and the triptans in treating acute migraine bolstered the vascular theory, but evidence is now emerging that vasodilatation is neither necessary nor sufficient to induce a migraine attack. Attention is now turning to the core migraine circuits in the brain, which include the trigeminal ganglia, trigeminal nucleus, medullary modulatory regions, pons, periaqueductal gray matter, hypothalamus and thalamus. Migraine triggers are likely to reflect a disturbance in overall balance of the circuits involved in the modulation of sensory activity, particularly those with relevance to the head. In this Review, we consider the evidence pointing towards a neuronal mechanism in migraine development, highlighting the role of calcitonin gene-related peptide (CGRP), which is found in small to medium-sized neurons in the trigeminal ganglion. CGRP is released during migraine attacks and can trigger migraine in patients, and CGRP receptor antagonists can abort migraine. We also examine whether other drugs, such as triptans, might exert their antimigraine effects via their actions on the neuronal circuit as opposed to the intracranial vasculature.

Key Points

  • Migraine pathophysiology involves complex peripheral and central processes

  • Neither vasodilatation nor neurogenic inflammation alone is sufficient to explain migraine pathophysiology

  • The brains of patients with migraine are susceptible to activation by various triggers that do not affect non-migraineurs

  • The sensitivity of migraineurs to specific triggers possibly has a genetic basis

  • Calcitonin gene-related peptide seems to have a central role in migraine pathogenesis through both peripheral and central mechanisms

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Migraine as a deficit in filtering of sensory inputs—a model.

Similar content being viewed by others

References

  1. Willis, T. The Anatomy of the Brain and Nerves (McGill University Press, Montreal, 1664).

    Google Scholar 

  2. Wolff, H. G. Headache and Other Head Pain (Oxford University Press, New York, 1948).

    Google Scholar 

  3. Gowers, W. R. In A Manual of Diseases of the Nervous System, 1357 (P. Blakiston Son & Co., Philadelphia, 1888).

    Google Scholar 

  4. Liveing, E. On Megrim, Sick-Headache, and Some Allied Disorders. A Contribution to the Pathology of Nerve-Storms (Arts & Boeve Nijmegen, London, 1873).

    Google Scholar 

  5. Moskowitz, M. A. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol. Sci. 13, 307–311 (1992).

    CAS  PubMed  Google Scholar 

  6. Humphrey, P. P. et al. Serotonin and migraine. Ann. NY Acad. Sci. 600, 587–598 (1990).

    CAS  PubMed  Google Scholar 

  7. Ferrari, M. D., Roon, K. I., Lipton, R. B. & Goadsby, P. J. Oral triptans (serotonin, 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 358, 1668–1675 (2001).

    CAS  PubMed  Google Scholar 

  8. Ho, T. et al. Randomized controlled trial of an oral CGRP antagonist, MK-0974, in acute treatment of migraine. Neurology 70, 1004–1012 (2008).

    Google Scholar 

  9. Olesen, J. et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N. Engl. J. Med. 350, 1104–1110 (2004).

    CAS  PubMed  Google Scholar 

  10. Bussone, G., Diener, H. C., Pfeil, J. & Schwalen, S. Topiramate 100 mg/day in migraine prevention: a pooled analysis of double-blinded randomised controlled trials. Int. J. Clin. Pract. 59, 961–968 (2005).

    CAS  PubMed  Google Scholar 

  11. Graham, J. R. & Wolff, H. G. Mechanism of migraine headache and action of ergotamine tartrate. Arch. Neurol. Psychiatry 39, 737–763 (1938).

    CAS  Google Scholar 

  12. Moskowitz, M. A. The neurobiology of vascular head pain. Ann. Neurol. 16, 157–168 (1984).

    CAS  PubMed  Google Scholar 

  13. Ray, B. S. & Wolff, H. G. Experimental studies on headache. Pain sensitive structures of the head and their significance in headache. Arch. Surg. 41, 813–856 (1940).

    Google Scholar 

  14. Olesen, J. et al. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann. Neurol. 28, 791–798 (1990).

    CAS  PubMed  Google Scholar 

  15. Olesen, J. Cerebral and extracranial circulatory disturbances in migraine: pathophysiological implications. Cerebrovasc. Brain Metab. Rev. 3, 1–28 (1991).

    CAS  PubMed  Google Scholar 

  16. Sanchez del Rio, M. et al. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 19, 701–707 (1999).

    CAS  PubMed  Google Scholar 

  17. Jansen, I., Goadsby, P. J., Uddman, R. & Edvinsson, L. Vasoactive intestinal peptide (VIP) like peptides in the cerebral circulation. J. Auton. Nerv. Syst. 49, S97–S103 (1994).

    Google Scholar 

  18. Rahmann, A. et al. Vasoactive intestinal peptide causes marked cephalic vasodilatation but does not induce migraine. Cephalalgia 28, 226–236 (2007).

    Google Scholar 

  19. Uddman, R., Goadsby, P. J., Jansen, I. & Edvinsson, L. PACAP, a VIP-like peptide, immunohistochemical localization and effect upon cat pial arteries and cerebral blood flow. J. Cereb. Blood Flow Metab. 13, 291–297 (1993).

    CAS  PubMed  Google Scholar 

  20. Henrik, S. et al. PACAP38 induces migraine-like attacks and vasodilatation—a causative role in migraine pathogenesis? Brain 132, 16–25 (2009).

    Google Scholar 

  21. Kruuse, C., Thomsen, L. L., Birk, S. & Olesen, J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 126, 241–247 (2003).

    PubMed  Google Scholar 

  22. Iversen, H. K., Olesen, J. & Tfelt-Hansen, P. Intravenous nitroglycerin as an experimental headache model. Basic characteristics. Pain 38, 17–24 (1989).

    CAS  PubMed  Google Scholar 

  23. Schoonman, G. G. et al. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study. Brain 131, 2192–2200 (2008).

    CAS  PubMed  Google Scholar 

  24. Goadsby, P. J. The vascular theory of migraine—a great story wrecked by the facts. Brain 132, 6–7 (2009).

    PubMed  Google Scholar 

  25. Moskowitz, M. A. & Cutrer, F. M. Sumatriptan: a receptor-targeted treatment for migraine. Annu. Rev. Med. 44, 145–154 (1993).

    CAS  PubMed  Google Scholar 

  26. Buzzi, M. G. & Moskowitz, M. A. The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br. J. Pharmacol. 99, 202–206 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Buzzi, M. G., Sakas, D. E. & Moskowitz, M. A. Indomethacin and acetylsalicylic acid block neurogenic plasma protein extravasation in rat dura mater. Eur. J. Pharmacol. 165, 251–258 (1989).

    CAS  PubMed  Google Scholar 

  28. Goadsby, P. J., Lipton, R. B. & Ferrari, M. D. Migraine—current understanding and treatment. N. Engl. J. Med. 346, 257–270 (2002).

    CAS  PubMed  Google Scholar 

  29. Lee, W. S. & Moskowitz, M. A. Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638, exhibit enhanced potency against neurogenic inflammation in dura mater. Brain Res. 626, 303–305 (1993).

    CAS  PubMed  Google Scholar 

  30. Giles, H. et al. Pre-clinical pharmacology of 4991W93, a potent inhibitor of neurogenic plasma protein extravasation [abstract]. Cephalalgia 19, 402 (1999).

    Google Scholar 

  31. Roon, K. I. 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. 47, 238–241 (2000).

    CAS  PubMed  Google Scholar 

  32. Earl, N. L., McDonald, S. A., Lowy, M. T. & 4991W93 Investigator Group. Efficacy and tolerability of the neurogenic inflammation inhibitor, 4991W93, in the acute treatment of migraine [abstract]. Cephalalgia 19, 357 (1999).

    Google Scholar 

  33. Diener, H. C. & RPR100893 Study Group. RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia 23, 183–185 (2003).

    PubMed  Google Scholar 

  34. Goldstein, D. J. et al. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia 17, 785–790 (1997).

    CAS  PubMed  Google Scholar 

  35. Connor, H. E. et al. Clinical evaluation of a novel, potent, CNS penetrating NK1 receptor antagonist in the acute treatment of migraine [abstract]. Cephalalgia 18, 392 (1998).

    Google Scholar 

  36. Norman, B., Panebianco, D. & Block, G. A. A placebo-controlled, in-clinic study to explore the preliminary safety and efficacy of intravenous L-758, 298 (a prodrug of the NK1 receptor antagonist L-754,030) in the acute treatment of migraine [abstract]. Cephalalgia 18, 407 (1998).

    Google Scholar 

  37. Goldstein, D. J. et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 21, 102–106 (2001).

    CAS  PubMed  Google Scholar 

  38. Lee, W. S., Moussaoui, S. M. & Moskowitz, M. A. Blockade by oral or parenteral RPR100893 (a non-peptide NK1 receptor antagonist) of neurogenic plasma protein extravasation in guinea-pig dura mater and conjunctiva. Br. J. Pharmacol. 112, 920–924 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. May, A. et al. Endothelin antagonist bosentan blocks neurogenic inflammation, but is not effective in aborting migraine attacks. Pain 67, 375–378 (1996).

    CAS  PubMed  Google Scholar 

  40. Limmroth, V., Lee, W. S., Cutrer, F. M. & Moskowitz, M. A. GABAA-receptor-mediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges. Br. J. Pharmacol. 117, 99–104 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Data, J. et al. A double-blind study of ganaxolone in the acute treatment of migraine headaches with or without an aura in premenopausal females [abstract]. Headache 38, 380 (1998).

    Google Scholar 

  42. Reuter, U. et al. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124, 2490–2502 (2001).

    CAS  PubMed  Google Scholar 

  43. De Alba, J. et al. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain 120, 170–181 (2006).

    CAS  PubMed  Google Scholar 

  44. Hoye, K. et al. Efficacy and tolerability of the iNOS inhibitor GW274150 administered up to 120 mg daily for 12 weeks in the prophylactic treatment of migraine [abstract]. Cephalalgia 29, 132 (2009).

    Google Scholar 

  45. Palmer, J. E. et al. A randomised, single-blind, placebo-controlled, adaptive clinical trial of GW274150, a selective iNOS inhibitor, in the treatment of acute migraine [abstract]. Cephalalgia 29, 124 (2009).

    Google Scholar 

  46. Levy, D., Burstein, R. & Strassman, A. M. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann. Neurol. 58, 698–705 (2005).

    CAS  PubMed  Google Scholar 

  47. Lennerz, J. K. 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. 507, 1277–1299 (2008).

    CAS  PubMed  Google Scholar 

  48. Goadsby, P. J., 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. 23, 193–196 (1988).

    CAS  PubMed  Google Scholar 

  49. Goadsby, P. J., Edvinsson, L. & Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187 (1990).

    CAS  PubMed  Google Scholar 

  50. Gallai, V. et al. Vasoactive peptides levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 15, 384–390 (1995).

    CAS  PubMed  Google Scholar 

  51. Knight, Y. E., Edvinsson, L. & Goadsby, P. J. Blockade of CGRP release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288. Neuropeptides 33, 41–46 (1999).

    CAS  PubMed  Google Scholar 

  52. Goadsby, P. J. & Edvinsson, L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann. Neurol. 33, 48–56 (1993).

    CAS  PubMed  Google Scholar 

  53. Lance, J. W. & Goadsby, P. J. (Eds) Mechanism and Management of Headache 7th edn (Elsevier, New York, 2005).

    Google Scholar 

  54. Ambrosini, A. & Schoenen, J. The electrophysiology of migraine. Curr. Opin. Neurol. 16, 327–331 (2003).

    PubMed  Google Scholar 

  55. Angelini, L. et al. Steady-state visual evoked potentials and phase synchronization in migraine patients. Phys. Rev. Lett. 93, 038103 (2004).

    CAS  PubMed  Google Scholar 

  56. Niebur, E., Hsiao, S. S. & Johnson, K. O. Synchrony: a neural mechanism for attentional selection? Curr. Opin. Neurobiol. 12, 190–194 (2002).

    CAS  PubMed  Google Scholar 

  57. Coppola, G. et al. Somatosensory evoked high-frequency oscillations reflecting thalamo-cortical activity are decreased in migraine patients between attacks. Brain 128, 98–103 (2005).

    PubMed  Google Scholar 

  58. Di Clemente, L. et al. Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine? Brain 130, 765–770 (2007).

    CAS  PubMed  Google Scholar 

  59. Ophoff, R. A. et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87, 543–552 (1996).

    CAS  PubMed  Google Scholar 

  60. De Fusco, M. et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nat. Genet. 33, 192–196 (2003).

    CAS  PubMed  Google Scholar 

  61. Dichgans, M. et al. Mutation in the neuronal voltage-gated sodium channel SCN1A causes familial hemiplegic migraine. Lancet 366, 371–377 (2005).

    CAS  PubMed  Google Scholar 

  62. Moskowitz, M. A., Bolay, H. & Dalkara, T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann. Neurol. 55, 276–280 (2004).

    CAS  PubMed  Google Scholar 

  63. Amara, S. G., Jonas, V., Rosenfeld, M. G., Ong, E. S. & Evans, R. M. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298, 240–244 (1982).

    CAS  PubMed  Google Scholar 

  64. Mulderry, P. K. et al. Differential expression of α-CGRP and β-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience 25, 195–205 (1988).

    CAS  PubMed  Google Scholar 

  65. Rosenfeld, M. G. et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue specific RNA processing. Nature 304, 129–135 (1983).

    CAS  PubMed  Google Scholar 

  66. Park, K. Y. & Russo, A. F. Control of the calcitonin gene-related peptide enhancer by upstream stimulatory factor in trigeminal ganglion neurons. J. Biol. Chem. 283, 5441–5451 (2008).

    CAS  PubMed  Google Scholar 

  67. Durham, P. L. et al. Neuronal expression and regulation of CGRP promoter activity following viral gene transfer into cultured trigeminal ganglia neurons. Brain Res. 997, 103–110 (2004).

    CAS  PubMed  Google Scholar 

  68. McLatchie, L. M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333–339 (1998).

    CAS  PubMed  Google Scholar 

  69. Hay, D. L., Conner, A. C., Howitt, S. G., Smith, D. M. & Poyner, D. R. The pharmacology of adrenomedullin receptors and their relationship to CGRP receptors. J. Mol. Neurosci. 22, 105–113 (2004).

    PubMed  Google Scholar 

  70. Marquez de Prado, B., Hammond, D. L. & Russo, A. F. Genetic enhancement of calcitonin gene-related peptide-induced central sensitization to mechanical stimuli in mice. J. Pain 10, 992–1000 (2009).

    CAS  PubMed  Google Scholar 

  71. Recober, A. et al. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. J. Neurosci. 29, 8798–8804 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hokfelt, T. et al. Calcitonin gene-related peptide in the brain, spinal cord, and some peripheral systems. Ann. NY Acad. Sci. 657, 119–134 (1992).

    CAS  PubMed  Google Scholar 

  73. Liu, Y., Zhang, M., Broman, J. & Edvinsson, L. Central projections of sensory innervation of the rat superficial temporal artery. Brain Res. 966, 126–133 (2003).

    CAS  PubMed  Google Scholar 

  74. Arbab, M. A., Delgado, T., Wiklund, L. & Svendgaard, N. A. 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, 54–63 (1988).

    CAS  PubMed  Google Scholar 

  75. Poyner, D. R. Calcitonin gene-related peptide: multiple actions, multiple receptors. Pharmacol. Ther. 56, 23–51 (1992).

    CAS  PubMed  Google Scholar 

  76. Gulbenkian, S., Uddman, R. & Edvinsson, L. Neuronal messengers in the cerebral circulation. Peptides 22, 995–1007 (2001).

    CAS  PubMed  Google Scholar 

  77. Gregg, K. V., Bishop, G. A. & King, J. S. Fine structural analysis of calcitonin gene-related peptide in the mouse inferior olivary complex. J. Neurocytol. 28, 431–438 (1999).

    CAS  PubMed  Google Scholar 

  78. Gendek-Kubiak, H. & Kmiec, B. L. Immunolocalization of CGRP, NPY and PGP 9.5 in guinea pig skin. Folia Morphol. (Warsz.) 63, 115–117 (2004).

    Google Scholar 

  79. Swartling, C., Naver, H., Pihl-Lundin, I., Hagforsen, E. & Vahlquist, A. Sweat gland morphology and periglandular innervation in essential palmar hyperhidrosis before and after treatment with intradermal botulinum toxin. J. Am. Acad. Dermatol. 51, 739–745 (2004).

    PubMed  Google Scholar 

  80. Fernandez, H. L. & Hodges-Savola, C. A. Physiological regulation of G4 AChe in fast-twitch muscle: effects of exercise and CGRP. J. Appl. Physiol. 80, 357–362 (1996).

    CAS  PubMed  Google Scholar 

  81. Palmer, J. B. et al. Calcitonin gene-related peptide is localised to human airway nerves and potently constricts human airway smooth muscle. Br. J. Pharmacol. 91, 95–101 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Hayakawa, T., Kuwahara, S., Maeda, S., Tanaka, K. & Seki, M. Distribution of vagal CGRP-immunoreactive fibers in the lower esophagus and the cardia of the stomach of the rat. J. Chem. Neuroanat. 38, 124–129 (2009).

    CAS  PubMed  Google Scholar 

  83. Rossi, S. G., Dickerson, I. M. & Rotundo, R. L. Localization of the calcitonin gene-related peptide receptor complex at the vertebrate neuromuscular junction and its role in regulating acetylcholinesterase expression. J. Biol. Chem. 278, 24994–25000 (2003).

    CAS  PubMed  Google Scholar 

  84. Todd, K. J. & Robitaille, R. Neuron–glia interactions at the neuromuscular synapse. Novartis Found. Symp. 276, 222–229 (2006).

    CAS  PubMed  Google Scholar 

  85. Al-Kazwini, S. J., Craig, R. K. & Marshall, I. Postjunctional inhibition of contractor responses in the mouse vas deferens by rat and human calcitonin gene-related peptides (CGRP). Br. J. Pharmacol. 88, 173–180 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Tarabal, O. et al. Regulation of motoneuronal calcitonin gene-related peptide (CGRP) during axonal growth and neuromuscular synaptic plasticity induced by botulinum toxin in rats. Eur. J. Neurosci. 8, 829–836 (1996).

    CAS  PubMed  Google Scholar 

  87. Tsukiji, J. et al. Long-term induction of β-CGRP mRNA in rat lungs by allergic inflammation. Life Sci. 76, 163–177 (2004).

    CAS  PubMed  Google Scholar 

  88. Ren, Y. H. et al. Temporal and spatial distribution of VIP, CGRP and their receptors in the development of airway hyperresponsiveness in the lungs. Sheng Li Xue Bao 56, 137–146 (2004).

    CAS  PubMed  Google Scholar 

  89. Rasmussen, T. N., Schmidt, P., Poulsen, S. S. & Holst, J. J. Effect of calcitonin gene-related peptide (CGRP) on motility and on the release of substance P, neurokinin A, somatostatin and gastrin in the isolated perfused porcine antrum. Neurogastroenterol. Motil. 13, 353–359 (2001).

    CAS  PubMed  Google Scholar 

  90. Edvinsson, L., Ekman, R., Jansen, I., McCulloch, J. & Uddman, R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J. Cereb. Blood Flow Metab. 7, 720–728 (1987).

    CAS  PubMed  Google Scholar 

  91. Uddman, R., Edvinsson, L., Ekblad, E., Hakanson, R. & Sundler, F. Calcitonin gene-related peptide (CGRP): perivascular distribution and vasodilatory effects. Regul. Pept. 15, 1–23 (1986).

    CAS  PubMed  Google Scholar 

  92. Liu, Y., Broman, J. & Edvinsson, L. Central projections of sensory innervation of the rat superior sagittal sinus. Neuroscience 129, 431–437 (2004).

    CAS  PubMed  Google Scholar 

  93. Liu, Y., Broman, J. & Edvinsson, L. Central projections of the sensory innervation of the rat middle meningeal artery. Brain Res. 1208, 103–110 (2008).

    CAS  PubMed  Google Scholar 

  94. Liu, Y., Broman, J., Zhang, M. & Edvinsson, L. Brainstem and thalamic projections from a craniovascular sensory nervous centre in the rostral cervical spinal dorsal horn of rats. Cephalalgia 29, 935–948 (2009).

    CAS  PubMed  Google Scholar 

  95. Oliver, K. R., Wainwright, A., Edvinsson, L., Pickard, J. D. & Hill, R. G. Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature. J. Cereb. Blood Flow Metab. 22, 620–629 (2002).

    CAS  PubMed  Google Scholar 

  96. Eftekhari, S. et al. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 169, 683–696 (2010).

    CAS  PubMed  Google Scholar 

  97. Gu, X. L. & Yu, L. C. The colocalization of CGRP receptor and AMPA receptor in the spinal dorsal horn neuron of rat: a morphological and electrophysiological study. Neurosci. Lett. 414, 237–241 (2007).

    CAS  PubMed  Google Scholar 

  98. Kong, L. L. & Yu, L. C. Involvement of mu- and delta-opioid receptors in the antinociceptive effects induced by AMPA receptor antagonist in the spinal cord of rats. Neurosci. Lett. 402, 180–183 (2006).

    CAS  PubMed  Google Scholar 

  99. Kong, L. & Yu, L. C. It is AMPA receptor, not kainate receptor, that contributes to the NBQX-induced antinociception in the spinal cord of rats. Brain Res. 1100, 73–77 (2006).

    CAS  PubMed  Google Scholar 

  100. Coggeshall, R. E. & Carlton, S. M. Receptor localization in the mammalian dorsal horn and primary afferent neurons. Brain Res. Rev. 24, 28–66 (1997).

    CAS  PubMed  Google Scholar 

  101. Nagy, G. G. et al. Widespread expression of the AMPA receptor GluR2 subunit at glutamatergic synapses in the rat spinal cord and phosphorylation of GluR1 in response to noxious stimulation revealed with an antigen-unmasking method. J. Neurosci. 24, 5766–5777 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Ebersberger, A., Charbel Issa, P., Vanegas, H. & Schaible, H. G. Differential effects of calcitonin gene-related peptide and calcitonin gene-related peptide 8–37 upon responses to N-methyl-D-aspartate or (R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate in spinal nociceptive neurons with knee joint input in the rat. Neuroscience 99, 171–178 (2000).

    CAS  PubMed  Google Scholar 

  103. Ramer, M. S., Bradbury, E. J., Michael, G. J., Lever, I. J. & McMahon, S. B. Glial cell line-derived neurotrophic factor increases calcitonin gene-related peptide immunoreactivity in sensory and motoneurons in vivo. Eur. J. Neurosci. 18, 2713–2721 (2003).

    PubMed  Google Scholar 

  104. Price, T. J. et al. Treatment of trigeminal ganglion neurons in vitro with NGF, GDNF or BDNF: effects on neuronal survival, neurochemical properties and TRPV1-mediated neuropeptide secretion. BMC Neurosci. 6, 4 (2005).

    PubMed  PubMed Central  Google Scholar 

  105. Di Angelantonio, S., Giniatullin, R., Costa, V., Sokolova, E. & Nistri, A. Modulation of neuronal nicotinic receptor function by the neuropeptides CGRP and substance P on autonomic nerve cells. Br. J. Pharmacol. 139, 1061–1073 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Yu, Y., Lundeberg, T. & Yu, L. C. Role of calcitonin gene-related peptide and its antagonist on the evoked discharge frequency of wide dynamic range neurons in the dorsal horn of the spinal cord in rats. Regul. Pept. 103, 23–27 (2002).

    CAS  PubMed  Google Scholar 

  107. Giniatullin, R., Nistri, A. & Fabbretti, E. Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol. Neurobiol. 37, 83–90 (2008).

    CAS  PubMed  Google Scholar 

  108. Sun, R. Q., Lawand, N. B. & Willis, W. D. The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin. Pain 104, 201–208 (2003).

    CAS  PubMed  Google Scholar 

  109. Pozo-Rosich, P., Storer, R. J. & Goadsby, P. J. Calcitonin gene-related peptide (CGRP) and its receptor antagonists BIBN4096BS (olcegepant) and CGRP (8–37) can modulate neuronal activity of the trigeminocervical complex of the rat when microinjected into the ventrolateral periaqueductal gray. Cephalalgia 29, 4–5 (2009).

    Google Scholar 

  110. Li, J., Vause, C. V. & Durham, P. L. Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Res. 1196, 22–32 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Morara, S. et al. Calcitonin gene-related peptide receptor expression in the neurons and glia of developing rat cerebellum: an autoradiographic and immunohistochemical analysis. Neuroscience 100, 381–391 (2000).

    CAS  PubMed  Google Scholar 

  112. Weiller, C. et al. Brain stem activation in spontaneous human migraine attacks. Nat. Med. 1, 658–660 (1995).

    CAS  PubMed  Google Scholar 

  113. Morara, S. et al. Calcitonin gene-related peptide (CGRP) triggers Ca2+ responses in cultured astrocytes and in Bergmann glial cells from cerebellar slices. Eur. J. Neurosci. 28, 2213–2220 (2008).

    PubMed  PubMed Central  Google Scholar 

  114. Sandor, P. S., Mascia, A., Seidel, L., de Pasqua, V. & Schoenen, J. Subclinical cerebellar impairment in the common types of migraine: a three-dimensional analysis of reaching movements. Ann. Neurol. 49, 668–672 (2001).

    CAS  PubMed  Google Scholar 

  115. Brighina, F. et al. Reduced cerebellar inhibition in migraine with aura: a TMS study. Cerebellum 8, 260–266 (2009).

    PubMed  Google Scholar 

  116. Pecile, A. et al. Calcitonin gene-related peptide: antinociceptive activity in rats, comparison with calcitonin. Regul. Pept. 18, 189–199 (1987).

    CAS  PubMed  Google Scholar 

  117. Huang, Y. H., Brodda-Jansen, G., Lundeberg, T. & Yu, L. C. Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone. Brain Res. 873, 54–59 (2000).

    CAS  PubMed  Google Scholar 

  118. Trang, T., Quirion, R. & Jhamandas, K. The spinal basis of opioid tolerance and physical dependence: Involvement of calcitonin gene-related peptide, substance P, and arachidonic acid-derived metabolites. Peptides 26, 1346–1355 (2005).

    CAS  PubMed  Google Scholar 

  119. Trang, T., Ma, W., Chabot, J. G., Quirion, R. & Jhamandas, K. Spinal modulation of calcitonin gene-related peptide by endocannabinoids in the development of opioid physical dependence. Pain 126, 256–271 (2006).

    CAS  PubMed  Google Scholar 

  120. Yallampalli, C. et al. Calcitonin gene-related peptide in pregnancy and its emergin receptor heterogeneity. Trends Endocrinol. Metab. 13, 263–269 (2002).

    CAS  PubMed  Google Scholar 

  121. Gangula, P. R. et al. Pregnancy and sex steroid hormones enhance circulating calcitonin gene-related peptide concentrations in rats. Human Reprod. 15, 949–953 (2000).

    CAS  Google Scholar 

  122. Williams, T. M. et al. Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead. Bioorg. Med. Chem. Lett. 16, 2595–2598 (2006).

    CAS  PubMed  Google Scholar 

  123. Salvatore, C. A. et al. Identification and pharmacological characterization of domains involved in binding of CGRP receptor antagonists to the calcitonin-like receptor. Biochemistry 45, 1881–1887 (2006).

    CAS  PubMed  Google Scholar 

  124. Connor, K. M. et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 73, 970–977 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Sur, C. et al. CSF levels and binding pattern of novel CGRP receptor antagonists in rhesus monkey and human central nervous system: toward the development of a PET tracer. Cephalalgia 29, 136–137 (2009).

    Google Scholar 

  126. Sinclair, S. R. et al. MK-0974 oral CGRP antagonist inhibits capsaicin-induced increase in dermal microvascular blood flow. Headache 47, 811 (2007).

    Google Scholar 

  127. Armstrong, G. A., Rodgers, C. I., Money, T. G. & Robertson, R. M. Suppression of spreading depression-like events in locusts by inhibition of the NO/cGMP/PKG pathway. J. Neurosci. 29, 8225–8235 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Longmore, J. et al. Differential distribution of 5HT1D- and 5HT1B-immunoreactivity within the human trigemino-cerebrovascular system: implications for the discovery of new antimigraine drugs. Cephalalgia 17, 833–842 (1997).

    CAS  PubMed  Google Scholar 

  129. Humphrey, P. P. & Goadsby, P. J. The mode of action of sumatriptan is vascular? A debate. Cephalalgia 14, 401–410 (1994).

    CAS  PubMed  Google Scholar 

  130. Nilsson, T., Longmore, J., Shaw, D., Jansen-Olesen, I. & Edvinsson, L. Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry. Br. J. Pharmacol. 128, 1133–1140 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Edvinsson, L. et al. Triptan-induced contractile (5-HT1B receptor) responses in human cerebral and coronary arteries: relationship to clinical effect. Clin. Sci. (Lond.) 109, 335–342 (2005).

    CAS  Google Scholar 

  132. Goadsby, P. J. & Hoskin, K. L. Serotonin inhibits trigeminal nucleus activity evoked by craniovascular stimulation through a 5-HT1B/1D receptor: a central action in migraine? Ann. Neurol. 43, 711–718 (1998).

    CAS  PubMed  Google Scholar 

  133. Goadsby, P. J. The pharmacology of headache. Prog. Neurobiol. 62, 509–525 (2000).

    CAS  PubMed  Google Scholar 

  134. Andreou, A. P., Holland, P. R. & Goadsby, P. J. Activation of iGluR5 kainate receptors inhibits neurogenic dural vasodilation in animal model of trigeminovascular activation. Br. J. Pharmacol. 157, 464–473 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Andreou, A. P. & Goadsby, P. J. Therapeutic potential of novel glutamate receptor antagonists in migraine. Expert Opin. Investig. Drugs 18, 789–803 (2009).

    CAS  PubMed  Google Scholar 

  136. Durham, P. L. & Russo, A. F. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J. Neurosci. 19, 3423–3429 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Levy, D., Jakubowski, M. & Burstein, R. Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT1B/1D receptor agonists. Proc. Natl Acad. Sci. USA 101, 4274–4279 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Hou, M. et al. 5-HT1B and 5-HT1D receptors in the human trigeminal ganglion: co-localization with calitonin gene-related peptide, substance P and nitric oxide synthase. Brain Res. 909, 112–120 (2001).

    CAS  PubMed  Google Scholar 

  139. Bartsch, T., Knight, Y. E. & Goadsby, P. J. Activation of 5-HT1B/1D receptors in the periaqueductal grey inhibits meningeal nociception. Ann. Neurol. 56, 371–381 (2004).

    CAS  PubMed  Google Scholar 

  140. Shields, K. G. & Goadsby, P. J. Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target? Neurobiol. Dis. 23, 491–501 (2006).

    CAS  PubMed  Google Scholar 

  141. Ferrari, M. D., van den Maagdenberg, A. M. J. M., Frants, R. R. & Goadsby, P. J. Migraine as a cerebral ionopathy with impaired central sensory processing. In Molecular Neurology (ed. Waxman, S. G.) 439–461 (Elsevier Academic Press, London, 2007).

    Google Scholar 

  142. Russell, M. B. & Olesen, J. Increased familial risk and evidence of genetic factor in migraine. BMJ 311, 541–544 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Ulrich, V., Russell, M. B., Østergaard, S. & Olesen, J. Analysis of 31 families with an apparently autosomal dominant transmission of migraine with aura in the nuclear families. Am. J. Med. Genet. 74, 395–397 (1997).

    CAS  PubMed  Google Scholar 

  144. Ulrich, V., Gervil, M., Kyvik, K. O., Olesen, J. & Russell, M. B. The inheritance of migraine with aura estimated by means of structural equation modelling. J. Med. Genet. 36, 225–227 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Uddman, R., Edvinsson, L., Ekman, R., Kingman, T. & McCulloch, J. 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, 131–136 (1985).

    CAS  PubMed  Google Scholar 

  146. Edvinsson, L., Fredholm, B. B., Hamel, E., Jansen, I. & Verrecchia, C. Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation of release of an endothelium-derived relaxing factor in the cat. Neurosci. Lett. 58, 213–217 (1985).

    CAS  PubMed  Google Scholar 

  147. Brain, S. D., Williams, T. J., Tippins, J. R., Morris, H. R. & MacIntyre, I. Calcitonin gene-related peptide is a potent vasodilator. Nature 313, 54–56 (1985).

    CAS  PubMed  Google Scholar 

  148. McCulloch, J., Uddman, R., Kingman, T. A. & Edvinsson, L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc. Natl Acad. Sci. USA 83, 1–5 (1986).

    Google Scholar 

  149. Edvinsson, L., Olesen, I., Kingman, T. A., McCulloch, J. & Uddman, R. Modification of vasoconstrictor responses in cerebral blood vessels by lesioning of the trigeminal nerve: possible involvement of CGRP. Cephalalgia 15, 373–383 (1995).

    CAS  PubMed  Google Scholar 

  150. Edvinsson, L., McCulloch, J., Kingman, T. A. & Uddman, R. On the functional role of the trigemino-cerebrovascular system in the regulation of cerebral circulation. In Neural Regulation of the Cerebral Circulation (eds Owman, C. & Hardebo, J. E.) 407–418 (Elsevier Science Publishers, B.V., Stockholm, 1986).

    Google Scholar 

  151. Goadsby, P. J. & Edvinsson, L. Human in vivo evidence for trigeminovascular activation in cluster headache. Brain 117, 427–434 (1994).

    PubMed  Google Scholar 

  152. Edvinsson, L. & Uddman, R. Neurobiology in primary headaches. Brain Res. Rev. 48, 438–456 (2005).

    PubMed  Google Scholar 

  153. Grunditz, T. et al. Calcitonin gene-related peptide in thyroid nerve fibres and C cells. Effects on thyroid hormone secretion and response to hypercalcaemia. Endocrinology 119, 2313–2324 (1986).

    CAS  PubMed  Google Scholar 

  154. Tajti, J., Uddman, R., Moller, S., Sundler, F. & Edvinsson, L. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J. Auton. Nerv. Syst. 76, 176–183 (1999).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

T. W. Ho, L. Edvinsson and P. J. Goadsby contributed equally to researching data for the article, discussion of content, writing, and reviewing and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Lars Edvinsson.

Ethics declarations

Competing interests

T. W. Ho is a Director at Merck Sharp & Dohme. The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ho, T., Edvinsson, L. & Goadsby, P. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol 6, 573–582 (2010). https://doi.org/10.1038/nrneurol.2010.127

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2010.127

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing