Top

CNS Drugs

Published in:

01-10-2001 | Leading Article

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

Therapeutic Implications

Author: Dr Lars Edvinsson

Published in: CNS Drugs | Issue 10/2001

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.

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

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

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

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

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

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

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

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: 131–6PubMedCrossRef

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: 193–6PubMedCrossRef

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: 310–6PubMedCrossRef

10.

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

11.

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

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: 5731–5PubMedCrossRef

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: 431–7PubMedCrossRef

14.

Goadsby PJ. Inhibition of calcitonin gene-related peptide byh-CGRP_8-37 antagonizes the cerebral dilator response fromnasociliary nerve stimulation in the cat. Neurosci Lett 1993; 151: 13–6PubMedCrossRef

15.

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

16.

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

17.

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

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: 48–56PubMedCrossRef

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

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: 212–8PubMedCrossRef

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: 384–90PubMed

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: 119–23PubMedCrossRef

23.

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

24.

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

25.

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

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): E331–5PubMed

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: 718–25PubMed

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: 1084–90PubMed

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: 59–66PubMedCrossRef

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: 1419–26PubMed

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: 11325–9PubMedCrossRef

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: 333–9PubMedCrossRef

33.

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

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: 29602–9PubMedCrossRef

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: 217–24PubMedCrossRef

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

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: 3455–60PubMedCrossRef

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: 31438–43PubMedCrossRef

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: 168–80CrossRef

40.

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

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: 209–11PubMedCrossRef

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: 176–83PubMedCrossRef

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: 41–4PubMedCrossRef

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): 420–3PubMedCrossRef

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: 39–44PubMedCrossRef

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: 875–84PubMedCrossRef

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: 313–9PubMedCrossRef

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: 768–75PubMed

49.

Hou M, Kanje M, Longmore J, et al. 5-HT_1B and 5-HT_1Dreceptors in the human trigeminal ganglion: co-localization with calcitonin gene-related peptide, substance P and nitric oxide synthase. Brain Res 2001; 909: 112–20PubMedCrossRef

Title: Calcitonin Gene-Related Peptide (CGRP) and the Pathophysiology of Headache
Therapeutic Implications
Author: Dr Lars Edvinsson
Publication date: 01-10-2001
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 10/2001
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.2165/00023210-200115100-00001

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Therapeutic Implications

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 10/2001

Severe Depression

Role of Estrogen in the Aetiology and Treatment of Mood Disorders

Sleep Disturbances in Patients with Alzheimer’s Disease

Design of Clinical Trials of Antidepressants