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pp 1-10 | Cite as

Role of CGRP in Migraine

  • Lars EdvinssonEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series

Abstract

Migraine is a common neurological disorder that afflicts up to 15% of the adult population in most countries, with predominance in females. It is characterized by episodic, often disabling headache, photophobia and phonophobia, autonomic symptoms (nausea and vomiting), and in a subgroup an aura in the beginning of the attack. Although still debated, many researchers consider migraine to be a disorder in which CNS dysfunction plays a pivotal role while various parts of the trigeminal system are necessary for the expression of associated symptoms.

Treatment of migraine has in recent years seen the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are now approved for use in frequent episodic and in chronic migraine. 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 have little or no adverse effects. Small molecule CGRP receptor antagonists, gepants, 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. The neurobiology of CGRP signaling is briefly summarized together with key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatments.

Keywords

CGRP CGRP receptor Gepants Migraine Monoclonal antibodies 

References

  1. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298:240–244Google Scholar
  2. Charles A (2018) The pathophysiology of migraine: implications for clinical management. Lancet Neurol 17:174–182Google Scholar
  3. Dodick DW (2018) Migraine. Lancet 391:1315–1330Google Scholar
  4. Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W (2000) Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 129:420–423Google Scholar
  5. Edvinsson L (1985) Functional-role of perivascular peptides in the control of cerebral-circulation. Trends Neurosci 8:126–131Google Scholar
  6. Edvinsson L (2011) Tracing neural connections to pain pathways with relevance to primary headaches. Cephalalgia 31:737–747Google Scholar
  7. Edvinsson L, Linde M (2010) New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet 376:645–655Google Scholar
  8. Edvinsson L, Uddman R (2005) Neurobiology in primary headaches. Brain Res Brain Res Rev 48:438–456Google Scholar
  9. Edvinsson LM, McCulloch J, Kingman TA, Uddman R (1986) On the functional role of the trigemino-cerebrovascular system in the regulation of the cerebral circulation. In: Owman CH, Hardebo JE (eds) Neural regulation of brain circulation. Elsevier, Amsterdam, pp 407–418Google Scholar
  10. Edvinsson L, Hara H, Uddman R (1989) Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides. J Cereb Blood Flow Metab 9:212–218Google Scholar
  11. Edvinsson L, Haanes KA, Warfvinge K, Krause DN (2018) CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol 14:338–350Google Scholar
  12. Eftekhari S, Edvinsson L (2011) Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci 12:112Google Scholar
  13. Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L (2010) Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 169:683–696Google Scholar
  14. Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L (2013) Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 14:1289–1303Google Scholar
  15. Egea SC, Dickerson IM (2012) Direct interactions between calcitonin-like receptor (CLR) and CGRP-receptor component protein (RCP) regulate CGRP receptor signaling. Endocrinology 153:1850–1860Google Scholar
  16. Goadsby PJ, Edvinsson L (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33:48–56Google Scholar
  17. Goadsby PJ, Edvinsson L, Ekman R (1988) Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 23:193–196Google Scholar
  18. Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28:183–187Google Scholar
  19. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S (2017) Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev 97:553–622Google Scholar
  20. Hara H, Jansen I, Ekman R, Hamel E, MacKenzie ET, Uddman R, Edvinsson L (1989) Acetylcholine and vasoactive intestinal peptide in cerebral blood vessels: effect of extirpation of the sphenopalatine ganglion. J Cereb Blood Flow Metab 9:204–211Google Scholar
  21. Hay DL, Garelja ML, Poyner DR, Walker CS (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol 175:3–17Google Scholar
  22. Holland PR, Goadsby PJ (2018) Targeted CGRP small molecule antagonists for acute migraine therapy. Neurotherapeutics 15:304–312Google Scholar
  23. Hou M, Kanje M, Longmore J, Tajti J, Uddman R, 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 Res 909:112–120Google Scholar
  24. Kim YG, Lone AM, Saghatelian A (2013) Analysis of the proteolysis of bioactive peptides using a peptidomics approach. Nat Protoc 8:1730–1742Google Scholar
  25. Kraenzlin ME, Ch’ng JL, Mulderry PK, Ghatei MA, Bloom SR (1985) 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 10:189–197Google Scholar
  26. Kuwasako K, Shimekake Y, Masuda M, Nakahara K, Yoshida T, Kitaura M, Kitamura K, Eto T, Sakata T (2000) Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling. J Biol Chem 275:29602–29609Google Scholar
  27. Liang YL, Khoshouei M, Deganutti G, Glukhova A, Koole C, Peat TS, Radjainia M, Plitzko JM, Baumeister W, Miller LJ et al (2018) Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature 561:492–497Google Scholar
  28. Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KR, Longmore J, Koblan KS, Kane SA (2002) Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists. J Biol Chem 277:14294–14298Google Scholar
  29. May A (2017) Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol Sci 38:125–130Google Scholar
  30. May A, Schulte LH (2016) Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol 12:455–464Google Scholar
  31. McCulloch J, Uddman R, Kingman TA, Edvinsson L (1986) Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A 83:5731–5735Google Scholar
  32. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339Google Scholar
  33. Padilla BE, Cottrell GS, Roosterman D, Pikios S, Muller L, Steinhoff M, Bunnett NW (2007) Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins. J Cell Biol 179:981–997Google Scholar
  34. Paone DV, Shaw AW, Nguyen DN, Burgey CS, Deng JZ, Kane SA, Koblan KS, Salvatore CA, Mosser SD, Johnston VK et al (2007) 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 50:5564–5567Google Scholar
  35. Russell FA, King R, Smillie SJ, Kodji X, Brain SD (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94:1099–1142Google Scholar
  36. Tajti J, Uddman R, Moller S, Sundler F, Edvinsson L (1999) Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst 76:176–183Google Scholar
  37. Uddman R, Edvinsson L (1989) Neuropeptides in the cerebral circulation. Cerebrovasc Brain Metab Rev 1:230–252Google Scholar
  38. Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J (1985) Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 62:131–136Google Scholar
  39. Uddman R, Edvinsson L, Ekblad E, Hakanson R, Sundler F (1986a) Calcitonin gene-related peptide (CGRP): perivascular distribution and vasodilatory effects. Regul Pept 15:1–23Google Scholar
  40. Uddman R, Edvinsson L, Jansen I, Stiernholm P, Jensen K, Olesen J, Sundler F (1986b) Peptide-containing nerve fibres in human extracranial tissue: a morphological basis for neuropeptide involvement in extracranial pain? Pain 27:391–399Google Scholar
  41. Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV, Coenen HH, Diener HC (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1:658–660Google Scholar
  42. Yarwood RE, Imlach WL, Lieu T, Veldhuis NA, Jensen DD, Klein Herenbrink C, Aurelio L, Cai Z, Christie MJ, Poole DP, Porter CJH, McLean P, Hicks GA, Geppetti P, Halls ML, Canals M, Bunnett NW (2017) Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission. Proc Natl Acad Sci U S A 114:12309–12314Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Experimental Vascular Research, Department of Clinical SciencesLund UniversityLundSweden
  2. 2.Department of Clinical Experimental ResearchGlostrup Research Institute, Glostrup HospitalGlostrupDenmark

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