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.
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
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Willis, T. The Anatomy of the Brain and Nerves (McGill University Press, Montreal, 1664).
Wolff, H. G. Headache and Other Head Pain (Oxford University Press, New York, 1948).
Gowers, W. R. In A Manual of Diseases of the Nervous System, 1357 (P. Blakiston Son & Co., Philadelphia, 1888).
Liveing, E. On Megrim, Sick-Headache, and Some Allied Disorders. A Contribution to the Pathology of Nerve-Storms (Arts & Boeve Nijmegen, London, 1873).
Moskowitz, M. A. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol. Sci. 13, 307–311 (1992).
Humphrey, P. P. et al. Serotonin and migraine. Ann. NY Acad. Sci. 600, 587–598 (1990).
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).
Ho, T. et al. Randomized controlled trial of an oral CGRP antagonist, MK-0974, in acute treatment of migraine. Neurology 70, 1004–1012 (2008).
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).
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).
Graham, J. R. & Wolff, H. G. Mechanism of migraine headache and action of ergotamine tartrate. Arch. Neurol. Psychiatry 39, 737–763 (1938).
Moskowitz, M. A. The neurobiology of vascular head pain. Ann. Neurol. 16, 157–168 (1984).
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).
Olesen, J. et al. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann. Neurol. 28, 791–798 (1990).
Olesen, J. Cerebral and extracranial circulatory disturbances in migraine: pathophysiological implications. Cerebrovasc. Brain Metab. Rev. 3, 1–28 (1991).
Sanchez del Rio, M. et al. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 19, 701–707 (1999).
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).
Rahmann, A. et al. Vasoactive intestinal peptide causes marked cephalic vasodilatation but does not induce migraine. Cephalalgia 28, 226–236 (2007).
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).
Henrik, S. et al. PACAP38 induces migraine-like attacks and vasodilatation—a causative role in migraine pathogenesis? Brain 132, 16–25 (2009).
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).
Iversen, H. K., Olesen, J. & Tfelt-Hansen, P. Intravenous nitroglycerin as an experimental headache model. Basic characteristics. Pain 38, 17–24 (1989).
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).
Goadsby, P. J. The vascular theory of migraine—a great story wrecked by the facts. Brain 132, 6–7 (2009).
Moskowitz, M. A. & Cutrer, F. M. Sumatriptan: a receptor-targeted treatment for migraine. Annu. Rev. Med. 44, 145–154 (1993).
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).
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).
Goadsby, P. J., Lipton, R. B. & Ferrari, M. D. Migraine—current understanding and treatment. N. Engl. J. Med. 346, 257–270 (2002).
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).
Giles, H. et al. Pre-clinical pharmacology of 4991W93, a potent inhibitor of neurogenic plasma protein extravasation [abstract]. Cephalalgia 19, 402 (1999).
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).
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).
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).
Goldstein, D. J. et al. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia 17, 785–790 (1997).
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).
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).
Goldstein, D. J. et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 21, 102–106 (2001).
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).
May, A. et al. Endothelin antagonist bosentan blocks neurogenic inflammation, but is not effective in aborting migraine attacks. Pain 67, 375–378 (1996).
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).
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).
Reuter, U. et al. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124, 2490–2502 (2001).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Lance, J. W. & Goadsby, P. J. (Eds) Mechanism and Management of Headache 7th edn (Elsevier, New York, 2005).
Ambrosini, A. & Schoenen, J. The electrophysiology of migraine. Curr. Opin. Neurol. 16, 327–331 (2003).
Angelini, L. et al. Steady-state visual evoked potentials and phase synchronization in migraine patients. Phys. Rev. Lett. 93, 038103 (2004).
Niebur, E., Hsiao, S. S. & Johnson, K. O. Synchrony: a neural mechanism for attentional selection? Curr. Opin. Neurobiol. 12, 190–194 (2002).
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).
Di Clemente, L. et al. Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine? Brain 130, 765–770 (2007).
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).
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).
Dichgans, M. et al. Mutation in the neuronal voltage-gated sodium channel SCN1A causes familial hemiplegic migraine. Lancet 366, 371–377 (2005).
Moskowitz, M. A., Bolay, H. & Dalkara, T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann. Neurol. 55, 276–280 (2004).
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).
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).
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).
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).
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).
McLatchie, L. M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333–339 (1998).
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).
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).
Recober, A. et al. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. J. Neurosci. 29, 8798–8804 (2009).
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).
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).
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).
Poyner, D. R. Calcitonin gene-related peptide: multiple actions, multiple receptors. Pharmacol. Ther. 56, 23–51 (1992).
Gulbenkian, S., Uddman, R. & Edvinsson, L. Neuronal messengers in the cerebral circulation. Peptides 22, 995–1007 (2001).
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).
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).
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).
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).
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).
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).
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).
Todd, K. J. & Robitaille, R. Neuron–glia interactions at the neuromuscular synapse. Novartis Found. Symp. 276, 222–229 (2006).
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).
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).
Tsukiji, J. et al. Long-term induction of β-CGRP mRNA in rat lungs by allergic inflammation. Life Sci. 76, 163–177 (2004).
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).
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).
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).
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).
Liu, Y., Broman, J. & Edvinsson, L. Central projections of sensory innervation of the rat superior sagittal sinus. Neuroscience 129, 431–437 (2004).
Liu, Y., Broman, J. & Edvinsson, L. Central projections of the sensory innervation of the rat middle meningeal artery. Brain Res. 1208, 103–110 (2008).
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).
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).
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).
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).
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).
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).
Coggeshall, R. E. & Carlton, S. M. Receptor localization in the mammalian dorsal horn and primary afferent neurons. Brain Res. Rev. 24, 28–66 (1997).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Weiller, C. et al. Brain stem activation in spontaneous human migraine attacks. Nat. Med. 1, 658–660 (1995).
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).
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).
Brighina, F. et al. Reduced cerebellar inhibition in migraine with aura: a TMS study. Cerebellum 8, 260–266 (2009).
Pecile, A. et al. Calcitonin gene-related peptide: antinociceptive activity in rats, comparison with calcitonin. Regul. Pept. 18, 189–199 (1987).
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).
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).
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).
Yallampalli, C. et al. Calcitonin gene-related peptide in pregnancy and its emergin receptor heterogeneity. Trends Endocrinol. Metab. 13, 263–269 (2002).
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).
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).
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).
Connor, K. M. et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 73, 970–977 (2009).
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).
Sinclair, S. R. et al. MK-0974 oral CGRP antagonist inhibits capsaicin-induced increase in dermal microvascular blood flow. Headache 47, 811 (2007).
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).
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).
Humphrey, P. P. & Goadsby, P. J. The mode of action of sumatriptan is vascular? A debate. Cephalalgia 14, 401–410 (1994).
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).
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).
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).
Goadsby, P. J. The pharmacology of headache. Prog. Neurobiol. 62, 509–525 (2000).
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).
Andreou, A. P. & Goadsby, P. J. Therapeutic potential of novel glutamate receptor antagonists in migraine. Expert Opin. Investig. Drugs 18, 789–803 (2009).
Durham, P. L. & Russo, A. F. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J. Neurosci. 19, 3423–3429 (1999).
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).
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).
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).
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).
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).
Russell, M. B. & Olesen, J. Increased familial risk and evidence of genetic factor in migraine. BMJ 311, 541–544 (1995).
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).
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).
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).
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).
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).
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).
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).
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).
Goadsby, P. J. & Edvinsson, L. Human in vivo evidence for trigeminovascular activation in cluster headache. Brain 117, 427–434 (1994).
Edvinsson, L. & Uddman, R. Neurobiology in primary headaches. Brain Res. Rev. 48, 438–456 (2005).
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).
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).
T. W. Ho is a Director at Merck Sharp & Dohme. The other authors declare no competing interests.
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
Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment
Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine: Evidence From Randomized Controlled Trials
Frontiers in Pharmacology (2020)
Galcanezumab in migraine prevention: a systematic review and meta-analysis of randomized controlled trials
Therapeutic Advances in Neurological Disorders (2020)
Placebo and nocebo phenomena in anti- CGRP monoclonal antibody trials for migraine prevention: a meta-analysis
Journal of Neurology (2020)
Journal of Neurology (2020)