Summary
In recent years, an increasing volume of evidence has suggested that the small messenger molecule nitric oxide (NO) plays a pivotal role in migraine pain. This evidence is mainly based on experimental studies using 2 different human headache models — intravenous infusion of nitroglycerin (glyceryl trinitrate) [a donor of NO] and intravenous infusion of histamine (which probably activates endothelial NO formation). These models offer unique possibilities for the study of NO mechanisms in migraine. Data suggest that NO is involved in the aetiology of migraine, a finding that may open up a number of possibilities for future drug treatments of the disorder.
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References
Culotta E, Koshland DE. No news is good news. Science 1992; 258: 1862–5
Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43: 109–41
Dawson TM, Dawson V, Snyder SH. A novel neuronal messenger molecule in brain: the free radical, nitric oxide. Ann Neurol 1992; 32: 297–311
Garthwaite J. Nitric oxide signalling in the nervous system. The Neurosciences 1993; 5: 171–80
Kerwin JF, Heller M. The arginine-nitric oxide pathway: a target for new drugs. Med Res Rev 1994; 14: 23–74
Nozaki K, Moskowitz MA, Maynard KI, et al. Possible origins and distribution of immunoactive nitric oxide synthase-containing nerve fibers in cerebral arteries. J Cereb Blood Flow Metab 1993; 13: 70–9
Friberg L, Olesen J, Iversen HK, et al. Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan. Lancet 1991; 338: 13–7
Thomsen LL, Iversen HK, Olesen J. Cerebral blood flow velocities are reduced during attacks of unilateral migraine without aura. Cephalalgia. In press
Iversen HK, Nielsen TH, Olesen J, et al. Arterial responses during migraine headache. Lancet 1990; 336: 837–9
Nichols FT III, Mawad M, Mohr JP, et al. Focal headache during balloon inflation in the internal carotid and middle cerebral arteries. Stroke 1990; 21: 555–9
Hibbs JB, Taintor RR, Vavrin Z, et al. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 1988; 157: 87–94
Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 1993; 52: 127–36
Garthwaite J, Charles SL, Chess-Williams R. Endotheliumderived relaxing factor release on activation of NMDA receptors suggests a role as intercellular messenger in the brain. Nature 1988; 336: 385–8
Kitto KF, Haley JE, Wilcox GL. Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neuroscience Lett 1992; 148: 1–5
Kolesnikov Ya, Pick CG, Pasternack GW. NG-nitro-1-arginine prevents morphine tolerance. Eur J Pharmacol 1992; 221: 399–400
Wei EP, Moskowitz MA, Baccalini P, et al. Calcitonin gene related peptide mediates nitroglycerin and sodium nitroprusside induced vasodilation in feline cerebral arterioles. Circulat Res 1992; 70: 1313–9
Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993; 43 Suppl. 3: S16–20
Goadsby P, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28: 183–7
Ignarro LJ, Lipton H, Edwards JC, et al. Mechanisms of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981; 218: 739–49
Gruetter CA, Kadowitz PJ, Ignarro LJ. Methylene blue inhibits coronary arterial relaxation and guanylate cyclase activation by nitroglycerin, sodium nitrate and amyl nitrate. Can J Physiol Pharmacol 1981; 59: 150–6
Feelisch M, Noack EA. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Pharmacol 1987; 139: 19–30
Harrison DG, Bates JN. The nitrovasodilators — new ideas about old drugs. Circulation 1993; 87: 1461–7
Iversen HK, Olesen J, Tfelt-Hansen P. Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 1989; 38: 17–24
Sicuteri F, Del Bene E, Poggioni M, et al. Unmasking latent dysnociception in healthy subjects. Headache 1987; 27: 180–5
Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity. A possible molecular mechanism of migraine pain. Neuroreport 1993; 4: 1027–30
Thomsen LL, Kruuse C, Iversen HK; et al. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1994; 1: 73–80
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8 Suppl. 7: 19–29
Dahl A, Russell D, Nyberg-Hansen R, et al. Effect of nitroglycerin on cerebral circulation measured by transcranial Doppler and SPECT. Stroke 1989; 20: 1733–6
Iversen HK, Holm S, Friberg L. Intracranial hemodynamics during intravenous nitroglycerin infusion. Cephalalgia 1989; 9 Suppl. 10: 84–5
Iversen HK. N-acetylcysteine enhances nitroglycerin-induced headache and cranial arterial responses. Clin Pharmacol Ther 1992; 52: 125–33
Thomsen LL, Iversen HK. Experimental and biological variation of three dimensional transcranial doppler measurements. J Appl Physiol 1993; 75: 2805–10
Busija DW, Heistad DD, Marcus ML. Continuous measurements of cerebral blood flow in anesthetized cats and dogs. Am J Physiol 1981; 241: H228–34
Thomsen LL, Iversen HK, Brinck TA, et al. Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers. Cephalalgia 1993; 13: 395–9
Lucher TF, Vanhoutte PM. The endothelium: modulator of cardiovascular functions. Ann Abor: CRC Press, 1990
Krabbe AA, Olesen J. Headache provocation by continuous intravenous infusion of histamine. Clinical results and receptor mechanisms. Pain 1980; 8: 253–9
De-Marinis M, Feliciani M, Janiri L, et al. Increased reactivity to a met-enkephalin analog in the control of autonomic responses in migraine patients. Clin Neuropharmacol 1990; 13: 507–21
Toda N. Mechanism underlying responses to histamine of isolated monkey and human cerebral arteries. Am J Physiol 1990; 258: H311–7
Ottossen ALP, Jansen I, Langemark M, et al. Histamine receptors in the isolated human middle meningeal artery. A comparison with cerebral and temporal arteries. Cephalalgia 1991; 11: 183–8
Iversen HK, Olesen J. The effect of histamine H1 blockade on nitroglycerin- (NTG)-induced headache and vascular responses [abstract]. Cephalalgia 1993; 13 Suppl. 13: 140
Goadsby PJ, Kaube H, Hoskin KL. Nitric oxide synthesis couples cerebral blood flow and metabolism. Brain Res 1992; 595: 167–70
Rees DD, Palmer RMJ, Schulz R, et al. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol 1990; 101: 746–52
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Thomsen, L.L., Iversen, H.K., Lassen, L.H. et al. The Role of Nitric Oxide in Migraine Pain. CNS Drugs 2, 417–422 (1994). https://doi.org/10.2165/00023210-199402060-00002
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DOI: https://doi.org/10.2165/00023210-199402060-00002