Calcitonin gene-related peptide (CGRP) levels during glyceryl trinitrate (GTN)-induced headache in healthy volunteers
Corresponding Author
C Kruuse
Danish Headache Centre and
Dr Christina Kruuse MD, PhD, Danish Headache Centre and Department of Neurology, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Copenhagen, Denmark. Tel. + 45-4323-2796, fax + 45-4323-3839, e-mail [email protected]Search for more papers by this authorI Jansen-Olesen
Department of Neurology, Clinical Experimental Research, University of Copenhagen and
Search for more papers by this authorL Edvinsson
Glostrup Hospital and Glostrup Research Park, Copenhagen, Denmark, and
Department of Internal Medicine, University Hospital Lund, Lund, Sweden
Search for more papers by this authorCorresponding Author
C Kruuse
Danish Headache Centre and
Dr Christina Kruuse MD, PhD, Danish Headache Centre and Department of Neurology, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Copenhagen, Denmark. Tel. + 45-4323-2796, fax + 45-4323-3839, e-mail [email protected]Search for more papers by this authorI Jansen-Olesen
Department of Neurology, Clinical Experimental Research, University of Copenhagen and
Search for more papers by this authorL Edvinsson
Glostrup Hospital and Glostrup Research Park, Copenhagen, Denmark, and
Department of Internal Medicine, University Hospital Lund, Lund, Sweden
Search for more papers by this authorAbstract
The role of nitric oxide (NO) in migraine has been studied in the experimental glyceryl trinitrate (GTN)-infusion headache model. We hypothesized that GTN-induced headache may activate the trigeminovascular system and be associated with increased levels of sensory neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers received subcutaneous sumatriptan 6 mg or placebo. This was succeeded by 20 min of GTN (0.12 µg kg−1 min−1) infusion. At baseline no subject reported headache (using verbal rating scale from 0 to 10) and the jugular CGRP-like immunoreactivity (-LI) level was 18.6 ± 2.5 pmol/l. After a 20-min intravenous infusion of GTN 0.12 µg kg−1 min−1, median peak headache intensity was 4 (range 2–6) (P < 0.05), while jugular CGRP-LI levels were unchanged (19.0 ± 2.8 pmol/l; P > 0.05). There were no changes in VIP-, NPY- or somatostatin-LI. In conclusion, the NO donor GTN appears not to induce headache via immediate CGRP release.
References
- 1 Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport 1993; 4: 1027–30.
- 2 Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1994; 1: 73–80.
- 3 Iversen HK. Experimental headache in humans. Cephalalgia 1995; 15: 281–7.
- 4 Afridi SK, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain 2004; 110: 675–80.
- 5 Edvinsson L. Neuronal signal substances as biomarkers of migraine. Headache 2006; 46: 1088–94.
- 6 Bellamy J, Bowen EJ, Russo AF, Durham PL. Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Eur J Neurosci 2006; 23: 2057–66.
- 7 Edvinsson L. CGRP-receptor antagonism in migraine treatment. Lancet 2008; 372(9656): 2089–90.
- 8 Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28: 183–7.
- 9 Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Glioti G 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.
- 10 Edvinsson L. Blockade of CGRP receptors in the intracranial vasculature: a new target in the treatment of headache. Cephalalgia 2004; 24: 611–22.
- 11 Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 2005; 25: 179–83.
- 12 Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J. No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol 2005; 58: 561–8.
- 13 Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004; 350: 1104–10.
- 14 Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008; 70: 1304–12.
- 15 Wei EP, Moskowitz MA, Boccalini P, Kontos HA. Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles. Circ Res 1992; 70: 1313–19.
- 16 Offenhauser N, Zinck T, Hoffmann J, Schiemann K, Schuh-Hofer S, Rohde W et al. CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia 2005; 25: 225–36.
- 17 Iversen HK, Olesen J, Tfelt Hansen P. Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 1989; 38: 17–24.
- 18 Nielsen TH, Iversen HK, Tfelt Hansen P, Olesen J. Small arteries can be accurately studied in vivo, using high frequency ultrasound. Ultrasound Med Biol 1993; 19: 717–25.
- 19 Iversen HK, Olesen J. Headache induced by a nitric oxide donor (nitroglycerin) responds to sumatriptan. A human model for development of migraine drugs. Cephalalgia 1996; 16: 412–18.
- 20 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: 427–34.
- 21 Juul R, Hara H, Gisvold SE, Brubakk AO, Fredriksen TA, Waldemar G et al. Alterations in perivascular dilatory neuropeptides (CGRP, SP, VIP) in the external jugular vein and in the cerebrospinal fluid following subarachnoid haemorrhage in man. Acta Neurochir (Wien) 1995; 132: 32–41.
- 22 Edvinsson L, Uddman R, Juul R. Peptidergic innervation of the cerebral circulation. Role in subarachnoid hemorrhage in man. Neurosurg Rev 1990; 13: 265–72.
- 23 Juul R, Edvinsson L, Gisvold SE, Ekman R, Brubakk AO, Fredriksen TA. Calcitonin gene-related peptide-LI in subarachnoid haemorrhage in man. Signs of activation of the trigemino-cerebrovascular system? Br J Neurosurg 1990; 4: 171–9.
- 24 Heilig M, Sjogren M, Blennow K, Ekman R, Wallin A. Cerebrospinal fluid neuropeptides in Alzheimer's disease and vascular dementia. Biol Psychiatry 1995; 38: 210–16.
- 25 Schoonman GG, Van Der Grond J, Kortmann C, Van Der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study. Brain 2008; 131: 2192–200.
- 26 De Hoon JN, Smits P, Troost J, Struijker-Boudier HA, Van Bortel LM. Forearm vascular response to nitric oxide and calcitonin gene-related peptide: comparison between migraine patients and control subjects. Cephalalgia 2006; 26: 56–63.
- 27 Nilsson T, Longmore J, Shaw D, Olesen IJ, Edvinsson L. Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry. Br J Pharmacol 1999; 128: 1133–40.
- 28 Hansen-Schwartz J, Lovland Hoel N, Nilsson E, Tfelt-Hansen P, Edvinsson L. Endothelium-dependent relaxant responses to selective 5-HT(1B/1D) receptor agonists in the isolated middle cerebral artery of the rat. J Vasc Res 2003; 40: 561–6.
- 29 Hoel NL, Hansen-Schwartz J, Edvinsson L. Selective up-regulation of 5-HT(1B/1D) receptors during organ culture of cerebral arteries. Neuroreport 2001; 12: 1605–8.
- 30 Juhasz G, Zsombok T, Modos EA, Olajos S, Jakab B, Nemeth J et al. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 2003; 106: 461–70.
- 31 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.
- 32 Kruuse C, Frandsen E, Schifter S, Thomsen L, Birk S, Olesen J. Plasma levels of cAMP, cGMP and CGRP in sildenafil-induced headache. Cephalalgia 2004; 24: 547–53.
