Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.
Multiple studies have confirmed that release of calcitonin gene-related peptide (CGRP) is increased during acute migraine attacks.
In the trigeminal ganglion, CGRP is expressed in C-fibres and its receptor is expressed in Aδ-fibres; these types of fibres are involved in different aspects of pain perception.
The trigeminal ganglion is central to the trigeminovascular reflex, which is triggered to protect against vasoconstriction; triggering of this system in patients with migraine leads to the perception of pain.
The trigeminal ganglion and dura are not behind the blood–brain barrier; therefore, they are likely to be the targets of gepants and antibodies in migraine treatment.
CGRP receptor antagonists, anti-CGRP antibodies and anti-CGRP receptor antibodies have proved effective for migraine pain relief, strongly supporting the hypothesis that CGRP has a major role in migraine pathophysiology.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Steiner, T. J., Stovner, L. J. & Birbeck, G. L. Migraine: the seventh disabler. Cephalalgia 33, 289–290 (2013).
Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: 2nd edition. Cephalalgia 24(Suppl. 1), 9–160 (2004).
Disease, G. B. D., Injury, I. & Prevalence, C. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet 390, 1211–1259 (2017).
Villalon, C. M. & van den Brink, A. M. The role of 5-hydroxytryptamine in the pathophysiology of migraine and its relevance to the design of novel treatments. Mini Rev. Med. Chem 17, 928–938 (2017).
Schuster, N. M. & Rapoport, A. M. New strategies for the treatment and prevention of primary headache disorders. Nat. Rev. Neurol. 12, 635–650 (2016).
Gonzalez-Hernandez, A., Marichal-Cancino, B. A., MaassenVanDenBrink, A. & Villalon, C. M. Side effects associated with current and prospective antimigraine pharmacotherapies. Expert Opin. Drug Metab. Toxicol. 14, 25–41 (2018).
Silberstein, S. D. et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the quality standards subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 78, 1337–1345 (2012).
Berger, A., Bloudek, L. M., Varon, S. F. & Oster, G. Adherence with migraine prophylaxis in clinical practice. Pain Pract. 12, 541–549 (2012).
Edvinsson, L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache 57(Suppl. 2), 47–55 (2017).
Schuster, N. M. & Rapoport, A. M. Calcitonin gene-related peptide-targeted therapies for migraine and cluster headache: a review. Clin. Neuropharmacol. 40, 169–174 (2017).
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).
Edvinsson, L. The journey to establish CGRP as a migraine target: a retrospective view. Headache 55, 1249–1255 (2015).
Russell, F. A., King, R., Smillie, S. J., Kodji, X. & Brain, S. D. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 94, 1099–1142 (2014).
Jansen-Olesen, I., Mortensen, A. & Edvinsson, L. Calcitonin gene-related peptide is released from capsaicin-sensitive nerve fibres and induces vasodilatation of human cerebral arteries concomitant with activation of adenylyl cyclase. Cephalalgia 16, 310–316 (1996).
Edvinsson, L., Jansen, I., Kingman, T. A. & McCulloch, J. Cerebrovascular responses to capsaicin in vitro and in situ. Br. J. Pharmacol. 100, 312–318 (1990).
Goadsby, P. J. & Edvinsson, L. Joint 1994 Wolff award presentation. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90. Headache 34, 394–399 (1994).
Edvinsson, L. & Goadsby, P. J. Neuropeptides in migraine and cluster headache. Cephalalgia 14, 320–327 (1994).
Durham, P. L. & Russo, A. F. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J. Neurosci. 19, 3423–3429 (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). In this study, the measurement of peptides after a migraine attack showed that only CGRP release was increased; subcutaneous sumatriptan normalized CGRP and concurrently reduced headache.
Amrutkar, D. V. et al. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system. Pain 153, 830–838 (2012).
Raffaelli, B., Israel, H., Neeb, L. & Reuter, U. The safety and efficacy of the 5-HT 1 F receptor agonist lasmiditan in the acute treatment of migraine. Expert Opin. Pharmacother. 18, 1409–1415 (2017).
Kim, Y. G., Lone, A. M. & Saghatelian, A. Analysis of the proteolysis of bioactive peptides using a peptidomics approach. Nat. Protoc. 8, 1730–1742 (2013).
Russo, A. F. Overview of neuropeptides: awakening the senses? Headache 57(Suppl. 2), 37–46 (2017).
Hoffmann, J., Wecker, S., Neeb, L., Dirnagl, U. & Reuter, U. Primary trigeminal afferents are the main source for stimulus-induced CGRP release into jugular vein blood and CSF. Cephalalgia 32, 659–667 (2012).
Goadsby, P. J., Edvinsson, L. & Ekman, R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann. Neurol. 23, 193–196 (1988).
Kraenzlin, M. E., Ch’ng, J. L., Mulderry, P. K., Ghatei, M. A. & Bloom, S. R. Infusion of a novel peptide, calcitonin gene-related peptide (CGRP) in man. Pharmacokinetics and effects on gastric acid secretion and on gastrointestinal hormones. Regul. Pept. 10, 189–197 (1985).
Hay, D. L., Garelja, M. L., Poyner, D. R. & Walker, C. S. Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br. J. Pharmacol. 175, 3–17 (2018).
McLatchie, L. M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333–339 (1998). This study illustrated the importance of RAMP1 for the function of the CGRP receptor for the first time.
Mallee, J. J. et al. Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists. J. Biol. Chem. 277, 14294–14298 (2002).
Hay, D. L. & Pioszak, A. A. Receptor activity-modifying proteins (RAMPs): new insights and roles. Annu. Rev. Pharmacol. Toxicol. 56, 469–487 (2016).
Egea, S. C. & Dickerson, I. M. Direct interactions between calcitonin-like receptor (CLR) and CGRP-receptor component protein (RCP) regulate CGRP receptor signaling. Endocrinology 153, 1850–1860 (2012).
Edvinsson, L., Fredholm, B. B., Hamel, E., Jansen, I. & Verrecchia, C. Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation or release of an endothelium-derived relaxing factor in the cat. Neurosci. Lett. 58, 213–217 (1985). This was the first study of the vascular relaxation effect of CGRP on cerebral vessels in parallel with intracellular increase of cAMP; the results show that CGRP dilations are independent of the presence of endothelium.
Padilla, B. E. et al. Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins. J. Cell Biol. 179, 981–997 (2007).
Walker, C. S. et al. A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann. Clin. Transl Neurol. 2, 595–608 (2015).
Edvinsson, L. Novel migraine therapy with calcitonin gene-regulated peptide receptor antagonists. Expert Opin. Ther. Targets 11, 1179–1188 (2007).
Edvinsson, L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br. J. Clin. Pharmacol. 80, 193–199 (2015).
Puledda, F., Messina, R. & Goadsby, P. J. An update on migraine: current understanding and future directions. J. Neurol. 264, 2031–2039 (2017).
Edvinsson, L., Villalon, C. M. & MaassenVanDenBrink, A. Basic mechanisms of migraine and its acute treatment. Pharmacol. Ther. 136, 319–333 (2012).
Edvinsson, L. & Petersen, K. A. CGRP-receptor antagonism in migraine treatment. CNS Neurol. Disord. Drug Targets 6, 240–246 (2007).
Doods, H. et al. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br. J. Pharmacol. 129, 420–423 (2000). This study is a pharmacological characterization of olcegepant, the first CGRP blocker.
Edvinsson, L. et al. Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells. Eur. J. Pharmacol. 434, 49–53 (2002).
Hay, D. L. & Poyner, D. The preclinical pharmacology of BIBN4096BS, a CGRP antagonist. Cardiovasc. Drug Rev. 23, 31–42 (2005).
Petersen, K. A., Nilsson, E., Olesen, J. & Edvinsson, L. Presence and function of the calcitonin gene-related peptide receptor on rat pial arteries investigated in vitro and in vivo. Cephalalgia 25, 424–432 (2005).
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). This paper presents the first clinical application of olcegepant for acute migraine, showing good acute and long-term effects.
Ho, T. W. et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 372, 2115–2123 (2008).
Connor, K. M. et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 73, 970–977 (2009).
Paone, D. V. et al. Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: discovery of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl) azepan-3-yl]-4- (2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974). J. Med. Chem. 50, 5564–5567 (2007).
Edvinsson, L. & Linde, M. New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet 376, 645–655 (2010).
Voss, T. et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 36, 887–898 (2016).
Hewitt, D. J. et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 31, 712–722 (2011).
Diener, H. C. et al. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 31, 573–584 (2011).
Marcus, R. et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34, 114–125 (2014).
Bell, I. M. Calcitonin gene-related peptide receptor antagonists: new therapeutic agents for migraine. J. Med. Chem. 57, 7838–7858 (2014).
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). This article was the first to demonstrate that CGRP and substance P are co-expressed in the trigeminal ganglion and that denervation of the trigeminal ganglion leads to loss of CGRP at the nerve terminals, directly proving the origin of the innervation.
Edvinsson, L., Ekman, R. & Ottosson, A. Demonstration of perivascular peptides and changes in concentration with age in man. Gerontology 32(Suppl. 1), 50–52 (1986).
Silberstein, S. D. et al. Fremanezumab for the preventive treatment of chronic migraine. N. Engl. J. Med. 377, 2113–2122 (2017).
Goadsby, P. J. et al. A controlled trial of erenumab for episodic migraine. N. Engl. J. Med. 377, 2123–2132 (2017).
Shi, L. et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J. Pharmacol. Exp. Ther. 356, 223–231 (2016).
Edvinsson, L. Functional-role of perivascular peptides in the control of cerebral-circulation. Trends Neurosciences 8, 126–131 (1985). This paper presents the first suggestion that CGRP is involved in migraine pathophysiology.
Edvinsson, L., Ekman, R., Jansen, I., Ottosson, A. & Uddman, R. Peptide-containing nerve fibers in human cerebral arteries: immunocytochemistry, radioimmunoassay, and in vitro pharmacology. Ann. Neurol. 21, 431–437 (1987).
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). This was the first study to show that CGRP is released, but other peptides are not, in association with migraine attacks.
Goadsby, P. J. & Edvinsson, L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 117, 427–434 (1994). This study demonstrates the involvement of CGRP and VIP (from the parasympathetic system) in cluster headache and illustrates the efficacy of sumatriptan.
Bellamy, J. L., Cady, R. K. & Durham, P. L. Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. Headache 46, 24–33 (2006).
Jang, M. U., Park, J. W., Kho, H. S., Chung, S. C. & Chung, J. W. Plasma and saliva levels of nerve growth factor and neuropeptides in chronic migraine patients. Oral Dis. 17, 187–193 (2011).
Cady, R. K., Vause, C. V., Ho, T. W., Bigal, M. E. & Durham, P. L. Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Headache 49, 1258–1266 (2009).
van Dongen, R. M. et al. Migraine biomarkers in cerebrospinal fluid: a systematic review and meta-analysis. Cephalalgia 37, 49–63 (2017).
Edvinsson, L., Ekman, R. & Goadsby, P. J. Measurement of vasoactive neuropeptides in biological materials: problems and pitfalls from 30 years of experience and novel future approaches. Cephalalgia 30, 761–766 (2010).
Lassen, L. H. et al. CGRP may play a causative role in migraine. Cephalalgia 22, 54–61 (2002).
Hansen, J. M., Hauge, A. W., Olesen, J. & Ashina, M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30, 1179–1186 (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02873221 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02828020 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02867709 (2018).
Tepper, S. et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 16, 425–434 (2017).
Ashina, M. et al. Erenumab (AMG 334) in episodic migraine: interim analysis of an ongoing open-label study. Neurology 89, 1237–1243 (2017).
Sun, H. et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 382–390 (2016).
Dodick, D. W. et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 13, 1100–1107 (2014).
Bigal, M. E. et al. TEV-48125 for the preventive treatment of chronic migraine: efficacy at early time points. Neurology 87, 41–48 (2016).
Dodick, D. W. et al. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 13, 885–892 (2014).
Mitsikostas, D. D. & Reuter, U. Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies. Curr. Opin. Neurol. 30, 272–280 (2017).
Hou, M. et al. The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis. J. Headache Pain 18, 42 (2017).
Bigal, M. E. et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 14, 1091–1100 (2015).
MaassenVanDenBrink, A., Meijer, J., Villalon, C. M. & Ferrari, M. D. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol. Sci. 37, 779–788 (2016).
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).
Juul, R. et al. Calcitonin gene-related peptide (human alpha-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage. Neurosci. Lett. 170, 67–70 (1994).
Aubdool, A. A. et al. A novel alpha-calcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure. Circulation 136, 367–383 (2017).
Depre, C. et al. Double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stable angina. Cephalalgia 37, 340 (2017).
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). The immunohistochemical experiments in this study demonstrate the presence of CGRP and the CGRP receptor components in subpopulations of the human trigeminal ganglion: CGRP in C-fibres and CALCRL and RAMP in Aδ-fibres.
Miller, S. et al. Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies. Neuroscience 328, 165–183 (2016).
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).
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).
Eftekhari, S. et al. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res. 1600, 93–109 (2015). This article presents the first suggestion that the BBB is important in understanding the target of current anti-migraine treatments.
Quartu, M. et al. TRPV1 receptor in the human trigeminal ganglion and spinal nucleus: immunohistochemical localization and comparison with the neuropeptides CGRP and SP. J. Anat. 229, 755–767 (2016).
Hou, M. et al. 5-HT(1B) and 5-HT(1D) receptors in the human trigeminal ganglion: co-localization with calcitonin gene-related peptide, substance P and nitric oxide synthase. Brain Res. 909, 112–120 (2001).
Eftekhari, S., Warfvinge, K., Blixt, F. W. & Edvinsson, L. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J. Pain 14, 1289–1303 (2013).
Melo-Carrillo, A. et al. Fremanezumab-a humanized monoclonal anti-CGRP antibody-inhibits thinly myelinated (Adelta) but not unmyelinated (c) meningeal nociceptors. J. Neurosci. 37, 10587–10596 (2017).
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).
Vause, C. V. & Durham, P. L. CGRP stimulation of iNOS and NO release from trigeminal ganglion glial cells involves mitogen-activated protein kinase pathways. J. Neurochem. 110, 811–821 (2009).
Thalakoti, S. et al. Neuron-glia signaling in trigeminal ganglion: implications for migraine pathology. Headache 47, 1008–1023 (2007). discussion 1024–1005.
De Corato, A. et al. Trigeminal satellite cells express functional calcitonin gene-related peptide receptors, whose activation enhances interleukin-1beta pro-inflammatory effects. J. Neuroimmunol. 237, 39–46 (2011).
Ceruti, S. et al. Calcitonin gene-related peptide-mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q Cav2.1 knock-in mice: implications for basic mechanisms of migraine pain. J. Neurosci. 31, 3638–3649 (2011).
Capuano, A. et al. Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Mol. Pain 5, 43 (2009).
Mason, R. T. et al. Release of the predicted calcitonin gene-related peptide from cultured rat trigeminal ganglion cells. Nature 308, 653–655 (1984).
Olesen, I. J. et al. The peptidergic innervation of the human superficial temporal artery: immunohistochemistry, ultrastructure, and vasomotility. Peptides 16, 275–287 (1995).
Erdling, A., Sheykhzade, M. & Edvinsson, L. Differential inhibitory response to telcagepant on alphaCGRP induced vasorelaxation and intracellular Ca2+ levels in the perfused and non-perfused isolated rat middle cerebral artery. J. Headache Pain 18, 61 (2017).
Edvinsson, L. et al. Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries. Cephalalgia 30, 1233–1240 (2010).
Edvinsson, L., Nilsson, E. & Jansen-Olesen, I. Inhibitory effect of BIBN4096BS, CGRP(8–37), a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery. Br. J. Pharmacol. 150, 633–640 (2007).
Sheykhzade, M. et al. Binding and functional pharmacological characteristics of gepant-type antagonists in rat brain and mesenteric arteries. Vascul Pharmacol. 90, 36–43 (2017).
McCulloch, J., Uddman, R., Kingman, T. A. & Edvinsson, L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc. Natl Acad. Sci. USA 83, 5731–5735 (1986). The first study to demonstrate the trigeminovascular reflex and its dependency on CGRP.
Edvinsson, L., Jansen 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).
Lv, X., Wu, Z. & Li, Y. Innervation of the cerebral dura mater. Neuroradiol J. 27, 293–298 (2014).
Lukács, M. et al. Dural administration of inflammatory soup or complete freund’s adjuvant induces activation and inflammatory response in the rat trigeminal ganglion. J. Headache Pain 16, 79 (2015).
Messlinger, K., Hanesch, U., Baumgartel, M., Trost, B. & Schmidt, R. F. Innervation of the dura mater encephali of cat and rat: ultrastructure and calcitonin gene-related peptide-like and substance P-like immunoreactivity. Anat. Embryol. 188, 219–237 (1993).
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).
Jansen-Olesen, I., Jorgensen, L., Engel, U. & Edvinsson, L. In-depth characterization of CGRP receptors in human intracranial arteries. Eur. J. Pharmacol. 481, 207–216 (2003).
Chiu, I. M., von Hehn, C. A. & Woolf, C. J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 15, 1063–1067 (2012).
Pietrobon, D. & Moskowitz, M. A. Pathophysiology of migraine. Annu. Rev. Physiol. 75, 365–391 (2013).
Ray, B. S. & Wolff, H. G. Experimental studies on headache: pain-sensitive structures of the head and their significance in headache. JAMA. Surg. 41, 813–856 (1940).
Dalessio, D. J. Wolff’s headache and other head pain (Oxford University Press, 1980).
Amin, F. M. et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 12, 454–461 (2013).
Wienecke, T., Olesen, J. & Ashina, M. Discrepancy between strong cephalic arterial dilatation and mild headache caused by prostaglandin D(2) (PGD(2)). Cephalalgia 31, 65–76 (2011).
Peroutka, S. J. Neurogenic inflammation and migraine: implications for the therapeutics. Mol. Interv. 5, 304 (2005).
Goadsby, P. J. et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol. Rev. 97, 553–622 (2017).
May, A. Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol. Sci. 38, 125–130 (2017).
Eftekhari, S. & Edvinsson, L. Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci. 12, 112 (2011).
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).
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).
Sugimoto, T., Fujiyoshi, Y., Xiao, C., He, Y. F. & Ichikawa, H. Central projection of calcitonin gene-related peptide (CGRP)- and substance P (SP)-immunoreactive trigeminal primary neurons in the rat. J. Comp. Neurol. 378, 425–442 (1997).
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).
Edvinsson, L. Tracing neural connections to pain pathways with relevance to primary headaches. Cephalalgia 31, 737–747 (2011).
Eftekhari, S. & Edvinsson, L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Ther. Adv. Neurol. Disord. 3, 369–378 (2010).
Eftekhari, S. et al. Localization of CGRP receptor components and receptor binding sites in rhesus monkey brainstem: a detailed study using in situ hybridization, immunofluorescence, and autoradiography. J. Comp. Neurol. 524, 90–118 (2016).
Warfvinge, K. & Edvinsson, L. Distribution of CGRP and CGRP receptor components in the rat brain. Cephalalgia, https://doi.org/10.1177/0333102417728873 (2017).
Saunders, N. R., Dziegielewska, K. M., Mollgard, K. & Habgood, M. D. Markers for blood-brain barrier integrity: how appropriate is Evans blue in the twenty-first century and what are the alternatives? Front. Neurosci. 9, 385 (2015).
Fenstermacher, J. D., Blasberg, R. G. & Patlak, C. S. Methods for quantifying the transport of drugs across brain barrier systems. Pharmacol. Ther. 14, 217–248 (1981).
Blasberg, R. G., Patlak, C. S. & Fenstermacher, J. D. Selection of experimental conditions for the accurate determination of blood–brain transfer constants from single-time experiments: a theoretical analysis. J. Cereb. Blood Flow Metab. 3, 215–225 (1983).
Lundblad, C., Haanes, K. A., Grande, G. & Edvinsson, L. Experimental inflammation following dural application of complete Freund’s adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage. J. Headache Pain 16, 91 (2015). This study quantifies the passage of molecules across the BBB from the circulation to cerebral and trigeminal structures, demonstrating that the trigeminal ganglion is >30-fold more permeable than CNS structures.
Akerman, S., Holland, P. R. & Goadsby, P. J. Diencephalic and brainstem mechanisms in migraine. Nat. Rev. Neurosci. 12, 570–584 (2011).
Edvinsson, L. & Tfelt-Hansen, P. The blood-brain barrier in migraine treatment. Cephalalgia 28, 1245–1258 (2008).
Weiller, C. et al. Brain stem activation in spontaneous human migraine attacks. Nat. Med. 1, 658–660 (1995).
Goadsby, P. J. The vascular theory of migraine — a great story wrecked by the facts. Brain 132, 6–7 (2009).
Ho, T. W., Edvinsson, L. & Goadsby, P. J. CGRP and its receptors provide new insights into migraine pathophysiology. Nat. Rev. Neurol. 6, 573–582 (2010).
Bigal, M. E., Walter, S. & Rapoport, A. M. Therapeutic antibodies against CGRP or its receptor. Br. J. Clin. Pharmacol. 79, 886–895 (2015).
Nature Reviews Neurology thanks H.-C. Diener, A. Rapoport, A. Russo and C. M. Villalón for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Edvinsson, L., Haanes, K.A., Warfvinge, K. et al. CGRP as the target of new migraine therapies — successful translation from bench to clinic. Nat Rev Neurol 14, 338–350 (2018). https://doi.org/10.1038/s41582-018-0003-1
Long-term safety and tolerability of eptinezumab in patients with chronic migraine: a 2-year, open-label, phase 3 trial
BMC Neurology (2021)
Journal of Translational Medicine (2021)
Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study)
The Journal of Headache and Pain (2021)
Petasin and isopetasin reduce CGRP release from trigeminal afferents indicating an inhibitory effect on TRPA1 and TRPV1 receptor channels
The Journal of Headache and Pain (2021)
Nature Reviews Neurology (2021)