Migraine is considered a neurovascular disease affecting more than 10% of the general population. Currently available drugs for the acute treatment of migraine are vasoconstrictors, which have limitations in their therapeutic use. The calcitonin gene-related peptide (CGRP) has a key role in migraine, where levels of CGRP are increased during acute migraine attacks. CGRP is expressed throughout the central and peripheral nervous system, consistent with control of vasodilatation and transmission of nociceptive information. In migraine, CGRP is released from the trigeminal system. At peripheral synapses CGRP results in vasodilatation via receptors on the smooth muscle cells. At central synapses, CGRP acts postjunctionally on second-order neurons to transmit pain centrally via the brainstem and midbrain to higher cortical pain regions. The recently developed CGRP-receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine attacks. A remaining question is their site of action. The CGRP-receptor components (calcitonin receptor-like receptor, receptor activity modifying protein 1 and receptor component protein) are found to colocalize in the smooth muscle cells of intracranial arteries and in large-sized neurons in the trigeminal ganglion. The CGRP receptor has also been localized within parts of the brain and the brainstem. The aim of this paper is to review recent localization studies of CGRP and its receptor components within the nervous system and to discuss whether these sites could be possible targets for the CGRP-receptor antagonists.
Bahra, A., Matharu, M.S., Buchel, C., Frackowiak, R.S. and Goadsby, P.J. ( 2001) Brainstem activation specific to migraine headache. Lancet357: 1016-1017.
2.
Barth, S.W., Riediger, T., Lutz, T.A. and Rechkemmer, G. ( 2004) Peripheral amylin activates circumventricular organs expressing calcitonin receptor a/B subtypes and receptor-activity modifying proteins in the rat. Brain Res997: 97-102.
3.
Bellamy, J.L., Cady, R.K. and Durham, P.L. ( 2006) Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. Headache46: 24-33.
4.
Brighina, F., Palermo, A., Panetta, M.L., Daniele, O., Aloisio, A., Cosentino, G. et al. (2009) Reduced cerebellar inhibition in migraine with aura: A TMS study. Cerebellum8: 260-266.
5.
Capuano, A., De Corato, A., Lisi, L., Tringali, G., Navarra, P. and Dello Russo, C. ( 2009) Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: Relevance for migraine pathology. Mol Pain5: 43.
6.
Chan, K., Edvinsson, L., Eftekhari, S., Kimblad, P.O., Kane, S., Lynch, J. et al. (2010) Characterization of the CGRP receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries. J Pharmacol Exp Ther334: 746-752.
7.
Connor, K.M., Shapiro, R.E., Diener, H.C., Lucas, S., Kost, J., Fan, X. et al. (2009) Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology73: 970-977.
8.
Cottrell, G.S., Roosterman, D., Marvizon, J.C., Song, B., Wick, E., Pikios, S. et al. (2005) Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat. J Comp Neurol490: 239-255.
Doods, H., Arndt, K., Rudolf, K. and Just, S. ( 2007) CGRP antagonists: Unravelling the role of CGRP in migraine . Trends Pharmacol Sci28: 580-587.
11.
Dublin, P. and Hanani, M. ( 2007) Satellite glial cells in sensory ganglia: Their possible contribution to inflammatory pain. Brain Behav Immun21: 592-598.
12.
Durham, P.L. ( 2006) Calcitonin gene-related peptide (CGRP) and migraine. Headache46(Suppl 1): S3-S8. Edvinsson, L. (2008) CGRP-receptor antagonism in migraine treatment. Lancet372: 2089-2090.
13.
Edvinsson, L., Brodin, E., Jansen, I. and Uddman, R. ( 1988) Neurokinin a in cerebral vessels: Characterization, localization and effects in vitro. Regul Pept20: 181-197.
14.
Edvinsson, L., Cantera, L., Jansen-Olesen, I. and Uddman, R. ( 1997) Expression of calcitonin gene-related peptide1 receptor mRNA in human trigeminal ganglia and cerebral arteries. Neurosci Lett229: 209-211.
15.
Edvinsson, L., Chan, K.Y., Eftekhari, S., Nilsson, E., De Vries, R., Säveland, H. et al. (2010) Effect of the calcitonin gene-related (CGRP) receptor antagonist telcagepant in human cranial arteries. Cephalalgia30: 1233-1240.
16.
Edvinsson, L., Ekman, R., Jansen, I., Mcculloch, J. and Uddman, R. ( 1987) Calcitonin gene-related peptide and cerebral blood vessels: Distribution and vasomotor effects. J Cereb Blood Flow Metab7: 720-728.
17.
Edvinsson, L., Fredholm, B.B., Hamel, E., Jansen, I. and Verrecchia, C. ( 1985) 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 Lett58: 213-217.
18.
Edvinsson, L. and Goadsby, P.J. ( 1990) Extracerebral manifestations in migraine. A peptidergic involvement?J Intern Med228: 299-304.
19.
Edvinsson, L., Gulbenkian, S., Barroso, C.P., Cunhae Sa, E., Sa, M., Polak, J.M., Mortensen, A. et al. (1998) Innervation of the human middle meningeal artery: Immunohistochemistry, ultrastructure, and role of endothelium for vasomotility . Peptides19: 1213-1225.
20.
Edvinsson, L. and Ho, T.W.(2010b) CGRP receptor antagonism and migraine. Neurotherapeutics7: 164-175.
21.
Edvinsson, L. and Linde, M.(2010) New drugs in migraine treatment and prophylaxis: Telcagepant and topiramate . Lancet376: 645-655.
22.
Edvinsson, L. and Tfelt-Hansen, P. ( 2008) The blood-brain barrier in migraine treatment. Cephalalgia28: 1245-1258.
23.
Eftekhari, S. and Edvinsson, L. ( 2010) Immunoreactivity of calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus. In European Headache and Migraine Trust International Congress, October, abstract.
24.
Eftekhari, S., Edvinsson, L., Salvatore, C.A. and Warfvinge, K. ( 2010a) Cerebellar Distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) in rat. In European Headache and Migraine Trust International Congress, October, abstract.
25.
Eftekhari, S., Salvatore, C.A., Calamari, A., Kane, S.A., Tajti, J. and Edvinsson, L.(2010b) Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience169: 683-696.
26.
Evans, B.N., Rosenblatt, M.I., Mnayer, L.O., Oliver, K.R. and Dickerson, I.M. ( 2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem275: 31438-31443.
27.
Foord, S.M. and Marshall, F.H. ( 1999) RAMPs: Accessory proteins for seven transmembrane domain receptors. Trends Pharmacol Sci20: 184-187.
28.
Gibson, S.J., Polak, J.M., Bloom, S.R., Sabate, I.M., Mulderry, P.M., Ghatei, M.A. et al. (1984) Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species. J Neurosci4: 3101-3111.
29.
Goadsby, P.J. ( 2005) Advances in the understanding of headache. Br Med Bull73-74: 83-92.
30.
Goadsby, P.J. ( 2007) Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med13: 39-44.
31.
Goadsby, P.J. and Edvinsson, L. ( 1993) The trigeminovascular system and migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol33: 48-56.
32.
Goadsby, P.J., Edvinsson, L. and Ekman, R. ( 1988) Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol23: 193-196.
33.
Goadsby, P.J., Edvinsson, L. and Ekman, R. ( 1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol28: 183-187.
34.
Gregg, K.V., Bishop, G.A. and King, J.S. ( 1999) Fine structural analysis of calcitonin gene-related peptide in the mouse inferior olivary complex. J Neurocytol28: 431-438.
35.
Gulbenkian, S., Saetrum Opgaard, O., Ekman, R., Costa Andrade, N., Wharton, J., Polak, J.M. et al. (1993) Peptidergic innervation of human epicardial coronary arteries. Circ Res73: 579-588.
36.
Gulbenkian, S., Uddman, R. and Edvinsson, L. ( 2001) Neuronal messengers in the human cerebral circulation . Peptides22: 995-1007.
37.
Gupta, S., Mehrotra, S., Villalon, C.M., Garrelds, I.M., De Vries, R., Van Kats, J.P. et al. (2006) Characterisation of CGRP receptors in human and porcine isolated coronary arteries: Evidence for CGRP receptor heterogeneity . Eur J Pharmacol530: 107-116.
38.
Hagner, S., Haberberger, R., Kummer, W., Springer, J., Fischer, A., Bohm, S. et al. (2001) Immunohistochemical detection of calcitonin gene-related peptide receptor (CGRP)-1 in the endothelium of human coronary artery and bronchial blood vessels. Neuropeptides35: 58-64.
39.
Hanani, M. ( 2005) Satellite glial cells in sensory ganglia: From form to function. Brain Res Brain Res Rev48: 457-476.
40.
Hay, D.L., Poyner, D.R. and Quirion, R. ( 2008) International Union of Pharmacology. LXIX. Status of the calcitonin gene-related peptide subtype 2 receptor. Pharmacol Rev60: 143-145.
41.
Ho, T.W., Edvinsson, L. and Goadsby, P.J.(2010) CGRP receptor antagonism provides new insights into migraine pathophysiology . Nat Rev Neurol6: 573-582.
42.
Ho, T.W., Ferrari, M.D., Dodick, D.W., Galet, V., Kost, J., Fan, X. et al. (2008a) 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. Lancet372: 2115-2123.
43.
Ho, T.W., Mannix, L.K., Fan, X., Assaid, C., Furtek, C., Jones, C.J. et al. (2008b) Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine . Neurology70: 1304-1312.
44.
Hokfelt, T., Arvidsson, U., Ceccatelli, S., Cortes, R., Cullheim, S., Dagerlind, A. et al. (1992) Calcitonin gene-related peptide in the brain, spinal cord, and some peripheral systems. Ann N Y Acad Sci657: 119-134.
45.
Hou, M., Kanje, M., Longmore, J., Tajti, J., Uddman, R. and Edvinsson, L. ( 2001) 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 Res909: 112-120.
46.
Inagaki, S., Kito, S., Kubota, Y., Girgis, S., Hillyard, C.J. and Macintyre, I. ( 1986) Autoradiographic localization of calcitonin gene-related peptide binding sites in human and rat brains. Brain Res374: 287-298.
47.
Just, S., Arndt, K. and Doods, H. ( 2005) The role of CGRP and nicotinic receptors in centrally evoked facial blood flow changes. Neurosci Lett381: 120-124.
48.
Kawai, Y., Takami, K., Shiosaka, S., Emson, P.C., Hillyard, C.J., Girgis, S. et al. (1985) Topographic localization of calcitonin gene-related peptide in the rat brain: An immunohistochemical analysis. Neuroscience15: 747-763.
49.
Kristiansen, K.A. and Edvinsson, L. ( 2010) Neurogenic inflammation, a study of rat trigeminal ganglion . J Headache Pain; DOI 10.1007/s10194-010-0260-x.
50.
Lennerz, J.K., Ruhle, V., Ceppa, E.P., Neuhuber, W.L., Bunnett, N.W., Grady, E.F. et al. (2008) Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: Differences between peripheral and central CGRP receptor distribution. J Comp Neurol507: 1277-1299.
51.
Li, J., Vause, C.V. and Durham, P.L. ( 2008) Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Res1196: 22-32.
52.
Liu, Y., Broman, J., Zhang, M. and Edvinsson, L.(2009) Brainstem and thalamic projections from a craniovascular sensory nervous centre in the rostral cervical spinal dorsal horn of rats. Cephalalgia29: 935-948.
53.
Lynch, J., Regan, C., Edvinsson, L., Hargreaves, R. and Kane, S.(2010) Comparison of the vasoconstrictor effects of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (MK-0974) and zolmitriptan in human isolated coronary arteries. J Cardiovasc Pharmacol55: 518-521.
54.
Lynch, J.J., Shen, Y.T., Pittman, T.J., Anderson, K.D., Koblan, K.S., Gould, R.J. et al. (2009) Effects of the prototype serotonin 5-HT(1B/1D) receptor agonist sumatriptan and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37) on myocardial reactive hyperemic response in conscious dogs. Eur J Pharmacol623: 96-102.
55.
May, A. and Goadsby, P.J. ( 1999) The trigeminovascular system in humans: Pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab19: 115-127.
56.
Mclatchie, L.M., Fraser, N.J., Main, M.J., Wise, A., Brown, J., Thompson, N. et al. (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature393: 333-339.
57.
Morara, S., Provini, L. and Rosina, A. ( 1989) CGRP expression in the rat olivocerebellar system during postnatal development. Brain Res504: 315-319.
58.
Morara, S., Rosina, A., Provini, L., Forloni, G., Caretti, A. and Wimalawansa, S.J. ( 2000) Calcitonin gene-related peptide receptor expression in the neurons and glia of developing rat cerebellum: An autoradiographic and immunohistochemical analysis. Neuroscience100: 381-391.
59.
Morara, S., Van Der Want, J.J., De Weerd, H., Provini, L. and Rosina, A. ( 2001) Ultrastructural analysis of climbing fiber-Purkinje cell synaptogenesis in the rat cerebellum. Neuroscience108: 655-671.
60.
Morara, S., Wang, L.P., Filippov, V., Dickerson, I.M., Grohovaz, F., Provini, L. et al. (2008) Calcitonin gene-related peptide (CGRP) triggers Ca2+ responses in cultured astrocytes and in Bergmann glial cells from cerebellar slices. Eur J Neurosci28: 2213-2220.
61.
Morara, S., Wimalawansa, S.J. and Rosina, A. ( 1998) Monoclonal antibodies reveal expression of the CGRP receptor in Purkinje cells, interneurons and astrocytes of rat cerebellar cortex. Neuroreport9: 3755-3759.
62.
Moreno, M.J., Cohen, Z., Stanimirovic, D.B. and Hamel, E. ( 1999) Functional calcitonin gene-related peptide type 1 and adrenomedullin receptors in human trigeminal ganglia, brain vessels, and cerebromicrovascular or astroglial cells in culture. J Cereb Blood Flow Metab19: 1270-1278.
63.
Moskowitz, M.A. ( 1993) Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology43: S16-S20.
64.
Moskowitz, M.A., Reinhard Jr, J.F., Romero, J., Melamed, E. and Pettibone, D.J. ( 1979) Neurotransmitters and the fifth cranial nerve: Is there a relation to the headache phase of migraine? Lancet2: 883-885.
65.
Olesen, J., Diener, H.C., Husstedt, I.W., Goadsby, P.J., Hall, D., Meier, U. et al. (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med350: 1104-1110.
66.
Oliver, K.R., Kane, S.A., Salvatore, C.A., Mallee, J.J., Kinsey, A.M., Koblan, K.S. et al. (2001) Cloning, characterization and central nervous system distribution of receptor activity modifying proteins in the rat. Eur J Neurosci14: 618-628.
67.
Oliver, K.R., Wainwright, A., Edvinsson, L., Pickard, J.D. and Hill, R.G. ( 2002) Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature . J Cereb Blood Flow Metab22: 620-629.
68.
Pietrobon, D. ( 2007) Familial hemiplegic migraine. Neurotherapeutics4: 274-284.
Regan, C.P., Stump, G.L., Kane, S.A. and Lynch Jr, J.J. ( 2009) Calcitonin gene-related peptide receptor antagonism does not affect the severity of myocardial ischemia during atrial pacing in dogs with coronary artery stenosis. J Pharmacol Exp Ther328: 571-578.
71.
Sams, A. and Jansen-Olesen, I. ( 1998) Expression of calcitonin receptor-like receptor and receptor-activity-modifying proteins in human cranial arteries. Neurosci Lett258: 41-44.
72.
Sexton, P.M., Mckenzie, J.S. and Mendelsohn, F.A. ( 1988) Evidence for a new subclass of calcitonin/calcitonin gene-related peptide binding site in rat brain. Neurochem Int12: 323-335.
73.
Skofitsch, G. and Jacobowitz, D.M. ( 1985) Calcitonin gene-related peptide: Detailed immunohistochemical distribution in the central nervous system. Peptides6: 721-745.
74.
Smith, D., Hill, R.G., Edvinsson, L. and Longmore, J. ( 2002) An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres. Cephalalgia22: 424-431.
75.
Strata, P., Thach, W.T. and Ottersen, O.P.(2009) New insights in cerebellar function. Introduction. Neuroscience162: 545-548.
76.
Tajti, J., Uddman, R., Moller, S., Sundler, F. and Edvinsson, L. ( 1999) Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst76: 176-183.
77.
Thalakoti, S., Patil, V.V., Damodaram, S., Vause, C.V., Langford, L.E., Freeman, S.E. et al. (2007) Neuron-glia signaling in trigeminal ganglion: Implications for migraine pathology. Headache47: 1008-1023; discussion 1024-1025.
78.
Ueda, T., Ugawa, S., Saishin, Y. and Shimada, S. ( 2001) Expression of receptor-activity modifying protein (RAMP) mRNAs in the mouse brain. Brain Res Mol Brain Res93: 36-45.
79.
Unger, J.W. and Lange, W. ( 1991) Immunohistochemical mapping of neurophysins and calcitonin gene-related peptide in the human brainstem and cervical spinal cord. J Chem Neuroanat4: 299-309.
80.
Vause, C.V. and Durham, P.L.(2010) Calcitonin gene-related peptide differentially regulates gene and protein expression in trigeminal glia cells: Findings from array analysis. Neurosci Lett473: 163-167.
81.
Vincent, M. and Hadjikhani, N. ( 2007) The cerebellum and migraine. Headache47: 820-833.
82.
Weiller, C., May, A., Limmroth, V., Juptner, M., Kaube, H., Schayck, R.V. et al. (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med1: 658-660.
83.
Wolff, H.G. ( 1938) Headache and cranial arteries. Trans Assoc Am Physicians53: 193-198.
84.
Zhang, Z., Winborn, C.S., Marquez D.e Prado, B. and Russo, A.F. ( 2007) Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci27: 2693-2703.
