Skip to main content
SpringerLink
Log in

Calcitonin Gene-Related Peptide (CGRP) and the Pathophysiology of Headache

Therapeutic Implications

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Cerebral blood vessels are innervated by sensory nerves that store several neurotransmitters. In primary headaches, there is a clear association between head pain and the release of the neuropeptide calcitonin gene-related peptide (CGRP). Furthermore, when triptan antimigraine agents are administered, headache subsides and the neuropeptide release normalises, in part via a presynaptic effect.

The central role of CGRP in primary headaches has led to the search for suitable antagonists of the receptors for this neuropeptide, which it is hoped will have less cardiovascular adverse effects than the triptans. Recently, the initial pharmacological profile of such a group of compounds has been disclosed. These compounds are small molecules with high selectivity for human CGRP receptors. Hypothetically, these agents will be efficacious in the relief of migraine headaches via blockade of the effects of CGRP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Notes

  1. pA2 is the negative logarithm of the drug concentration causing a two-fold shift to the right of a dose-response curve.

References

  1. Amara SG, Jonas V, Rosenfeld MG, et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 1982; 298: 240–2

    Article  PubMed  CAS  Google Scholar 

  2. Sexton PM. Central nervous binding sites for calcitonin and calcitoningene-related peptide. Mol Neurobiol 1991; 5: 251–73

    Article  PubMed  CAS  Google Scholar 

  3. Brain SD, Cambridge H. Calcitonin gene-related peptide: vasoactive effects and potential therapeutic role. Gen Pharmacol 1996; 27: 607–11

    Article  PubMed  CAS  Google Scholar 

  4. Uddman R, Edvinsson L, Ekblad E, et al. Calcitonin gene-related peptide (CGRP): perivascular distribution and vasodilatory effects. Regul Pept 1986; 15: 1–23

    Article  PubMed  CAS  Google Scholar 

  5. Poyner D, Marshall I, Brain SD. The CGRP family: calcitonin gene-related peptide (CGRP), amylin and adrenomedullin. Georgetown (TX): Landes Bioscience, 2000: 1–261

    Google Scholar 

  6. Edvinsson L. Functional role of perivascular peptides in the control of the cerebral circulation. Trends Neurosci 1985; 8: 126–31

    Article  CAS  Google Scholar 

  7. Uddman R, Edvinsson L, Ekman R, et al. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 1985; 62: 131–6

    Article  PubMed  CAS  Google Scholar 

  8. Goadsby PJ, 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 1988; 23: 193–6

    Article  PubMed  CAS  Google Scholar 

  9. Jansen-Olesen I, Mortensen A, Edvinsson L, et al. Calcitonin gene-related peptide is released from capsaicin-sensitive nerve fibres and induces vasodilation of human cerebral arteries concomitant with activation of adenylyl cyclase. Cephalalgia 1996; 16: 310–6

    Article  PubMed  CAS  Google Scholar 

  10. Edvinsson L, Jansen I, Kingman TA, et al. Cerebrovascular responses to capsaicin in vitro and in situ. Br J Pharmacol 1990; 100: 312–8

    Article  PubMed  CAS  Google Scholar 

  11. Edvinsson L. Aspects on the pathophysiology of migraine and cluster headache. Pharmacol Toxicol 2001; 88: 65–73

    Article  Google Scholar 

  12. McCulloch J, Uddman R, Kingman TA, et al. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A 1986; 83: 5731–5

    Article  PubMed  CAS  Google Scholar 

  13. Edvinsson L, Ekman R, Jansen I, et al. Peptide-containing nerve fibers in human cerebral arteries: immunohistochemistry, radio-immunoassay and in vitro pharmacology. Ann Neurol 1987; 21: 431–7

    Article  PubMed  CAS  Google Scholar 

  14. Goadsby PJ. Inhibition of calcitonin gene-related peptide byh-CGRP8-37 antagonizes the cerebral dilator response fromnasociliary nerve stimulation in the cat. Neurosci Lett 1993; 151: 13–6

    Article  PubMed  CAS  Google Scholar 

  15. Gulbenkian S, Uddman R, Edvinsson L. Neuronal messengers in the human cerebral circulation. Peptides 2001; 22: 995–1007

    Article  PubMed  CAS  Google Scholar 

  16. Ray BS, Wolff HG. Experimental studies on headaches, pain sensitive structures of the head and their significance in headaches. Arch Surg 1940; 41: 813–56

    Article  Google Scholar 

  17. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28: 183–7

    Article  PubMed  CAS  Google Scholar 

  18. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33: 48–56

    Article  PubMed  CAS  Google Scholar 

  19. Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994; 117 Pt 3: 427–34

    Google Scholar 

  20. Edvinsson L, Hara H, Uddman R. Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides. J Cereb Blood Flow Metab 1989; 9: 212–8

    Article  PubMed  CAS  Google Scholar 

  21. Gallai V, Sarchielle P, Floridi A, et al. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 1995; 15: 384–90

    PubMed  CAS  Google Scholar 

  22. Fanciullacci M, Alessandri M, Figini M, et al. Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 1995; 60: 119–23

    Article  PubMed  CAS  Google Scholar 

  23. Fanciullacci M, Alessandri M, Sicuteri R, et al. Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients. Brain 1997; 120: 283–8

    Article  PubMed  Google Scholar 

  24. Goadsby PJ, Edvinsson L, Ekman R. Cutaneous sensory stimulation leading to facial flushing and release of calcitonin gene-related peptide. Cephalalgia 1992; 12: 53–6

    Article  PubMed  CAS  Google Scholar 

  25. Goadsby PJ, Edvinsson L. Neuropeptide changes in a case of chronic paroxysmal hemicrania: evidence for trigemino-parasympathetic activation. Cephalalgia 1996; 16: 448–50

    Article  PubMed  CAS  Google Scholar 

  26. Chiba T, Yamaguchi A, Yamatani T, et al. Calcitonin gene-related peptide receptor antagonist human CGRP(8-37). Am J Physiol 1989; 256(2 Pt 1): E331–5

    PubMed  CAS  Google Scholar 

  27. Dennis T, Fournier A, St Pierre S, et al. Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues.Evidence of receptor multiplicity. J Pharmacol Exp Ther 1989; 251: 718–25

    PubMed  CAS  Google Scholar 

  28. Mimeault M, Fournier A, Dumont Y, et al. Comparative affinities and antagonistic potencies of various human calcitonin gene-related peptide fragments on calcitonin gene-related peptide receptors in brain and periphery. J Pharmacol Exp Ther 1991; 258: 1084–90

    PubMed  CAS  Google Scholar 

  29. Dennis T, Fournier A, Guard S, et al. Calcitonin gene-related peptide (hCGRP alpha) binding sites in the nucleus accumbens. Atypical structural requirements and marked phylogenic differences. Brain Res 1991; 539: 59–66

    Article  PubMed  CAS  Google Scholar 

  30. Waugh DJ, Bockman J, Smith CS, et al. Limitations in using peptide drugs to characterize calcitonin gene-related peptide receptors. J Pharmacol Exp Ther 1999; 289: 1419–26

    PubMed  CAS  Google Scholar 

  31. Aiyar N, Rand K, Elshourbagy NA, et al. A cDNA encoding the calcitonin gene-related peptide type I receptor. J Biol Chem 1996; 271: 11325–9

    Article  PubMed  CAS  Google Scholar 

  32. McLatchie LM, Fraser NJ, Main MJ, et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1998; 393: 333–9

    Article  PubMed  CAS  Google Scholar 

  33. Foord SM, Marshall FH. RAMPs: accessory proteins for seven transmembrane domain receptors. Trends Pharmacol Sci 1999; 20: 184–7

    Article  PubMed  CAS  Google Scholar 

  34. Kuwasako K, Shimekake Y, Masuda M, et al. Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling. J Biol Chem 2000; 275: 29602–9

    Article  PubMed  CAS  Google Scholar 

  35. Armour SL, Foord S, Kenakin T, et al. Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor. J Pharmacol Toxicol Methods 1999; 42: 217–24

    Article  PubMed  CAS  Google Scholar 

  36. Christopolous G, Perry KJ, Morfis M, et al. Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Mol Pharmacol 1999; 56: 235–42

    Google Scholar 

  37. Luebke AE, Dahl GP, Roos BA, et al. Identification of a protein that confers calcitonin gene-related peptide responsiveness to oocytes by using a cystic fibrosis transmembrane conductance regulator assay. Proc Natl Acad Sci U S A 1996; 93: 3455–60

    Article  PubMed  CAS  Google Scholar 

  38. Evans BN, Rosenblatt MI, Mayer LO, et al. CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem 2000; 275: 31438–43

    Article  PubMed  CAS  Google Scholar 

  39. Edvinsson L, Goadsby PJ, Uddman R. Amylin: localization, effects on cerebral arteries and on local cerebral blood flow in the cat. Sci World 2001; 1: 168–80

    Article  CAS  Google Scholar 

  40. Jansen-Olesen I, Kaarill L, Edvinsson L. Characterization of CGRP1 receptors in the guinea pig basilar artery. Eur J Pharmacol 2001; 414: 249–58

    Article  PubMed  CAS  Google Scholar 

  41. Edvinsson L, Cantera L, Jansen-Olesen I, et al. Expression of calcitonin gene-related peptide 1 receptor mRNA in human trigeminal ganglia and cerebral arteries. Neurosci Lett 1997; 229: 209–11

    Article  PubMed  CAS  Google Scholar 

  42. Tajti J, Uddman R, Möller S, et al. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst 1999; 76: 176–83

    Article  PubMed  CAS  Google Scholar 

  43. Sams A, Jansen-Olesen I. Expression of calcitonin receptor-like receptor (CRLR) and receptor-activity-modifying proteins in human cranial arteries. Neurosci Lett 1998; 258: 41–4

    Article  PubMed  CAS  Google Scholar 

  44. Doods H, Hallermayer G, Wu D, et al. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 2000; 129(3): 420–3

    Article  PubMed  CAS  Google Scholar 

  45. Edvinsson L, Sams A, Jansen-Olesen I, et al. Characterization of the effects of a non-peptide CGRP receptor antagonist in SK-N-MC cells and isolated human cerebral arteries. Eur J Pharmacol 2001; 415: 39–44

    Article  PubMed  CAS  Google Scholar 

  46. Powell KJ, Ma W, Sutak M, et al. Blockade and reversal of spinal morphine tolerance by peptide and non-peptide calcitonin gene-related peptide receptor antagonists. Br J Pharmacol 2000; 131: 875–84

    Article  PubMed  CAS  Google Scholar 

  47. Wu D, Eberlein W, Rudolf K, et al. Characterisation of calcitonin gene-related peptide receptors in rat atrium and vas deferens:evidence for a [Cys(Et)2,7]hCGRP-preferring receptor. Eur J Pharmacol 2000; 400: 313–9

    Article  PubMed  CAS  Google Scholar 

  48. Aiyar N, Daines RA, Disa J, et al. Pharmacology of SB-273779, a nonpeptide calcitonin gene-related peptide 1 receptor antagonist. J Pharmacol Exp Ther 2001; 296: 768–75

    PubMed  CAS  Google Scholar 

  49. Hou M, Kanje M, Longmore J, et al. 5-HT1B and 5-HT1Dreceptors in the human trigeminal ganglion: co-localization with calcitonin gene-related peptide, substance P and nitric oxide synthase. Brain Res 2001; 909: 112–20

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The studies of the authors’ reviewed have been supported by the Swedish Research Council (project no. 5958).

Dr Edvinsson has no potential conflicts of interest that are directly relevant to the contents of this article.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Lund University Hospital, S-221 85, Lund, Sweden

    Lars Edvinsson

Authors
  1. Lars Edvinsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lars Edvinsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Edvinsson, L. Calcitonin Gene-Related Peptide (CGRP) and the Pathophysiology of Headache. Mol Diag Ther 15, 745–753 (2001). https://doi.org/10.2165/00023210-200115100-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-200115100-00001

Keywords

Search

Navigation