Glyceryl Trinitrate Induces Attacks of Migraine Without Aura in Sufferers of Migraine with Aura

Christiansen, I; Thomsen, Laura H.; Daugaard, D.; Ulrich, Vibeke; Olesen, Jes

doi:10.1046/j.1468-2982.1999.019007660.x

Cited by 177 publications

(177 citation statements)

References 31 publications

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“…36 However, an attack fulfilling criteria for migraine without aura developed in 6 of 12 patients. 35 This was significantly more than in the normal controls in which no one developed a migraine attack. It was concluded that GTN can not induce an aura, but patients having migraine with aura are more prone to develop a migraine attack without aura than normal controls.…”

Section: Migrainementioning

confidence: 73%

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Nitric Oxide-Related Drug Targets in Headache

Olesen

2010

Neurotherapeutics

102

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Summary: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so-called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-nitromonomethylarginine effectively treats attacks of migraine without aura. Similar results have been obtained for chronic the tension-type headache and cluster headache. Inhibition of the breakdown of cyclic guanylate phosphate (cGMP) also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine.Similar evidence suggests an important role of NO in the tension-type headache and cluster headache.These very strong data from human experimentation make it highly likely that antagonizing NO effects will be effective in the treatment of primary headaches. Nonselective NOS inhibitors are likely to have side effects whereas selective compounds are now in early clinical trials. Antagonizing the rate limiting cofactor tetrahydrobiopterin seems another very likely new treatment. It is more unlikely that antagonism of cGMP or its formation will be feasible, but augmenting its breakdown via phosphodiesterase activation is a possibility, as well as other ways of inhibiting the NO-cGMP pathway.

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Section: Migrainementioning

confidence: 73%

“…Twelve sufferers of migraine with aura who never had attacks without aura were therefore compared to 14 healthy subjects. 35 Both groups received GTN (0.5 m/kg/min for 20 min). Aura symptoms were not elicited in any subject, but have subsequently been observed by others in rare instances after GTN.…”

Section: Migrainementioning

confidence: 99%

Nitric Oxide-Related Drug Targets in Headache

Olesen

2010

Neurotherapeutics

102

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“…The average number of CGRP-positive neurons in the saline-treated animals was 53 AE 5 per slice, in the GTN-treated animals 93 AE 4 (p ¼ .028; Figure 2A). The increase in CGRP-immunopositive cells after GTN treatment was found both in V1 and in V2/3 (ANOVA F (1,8) ¼ 6.4, p ¼ .035, HSD post-hoc tests both p < .001; Figure 3). The size of CGRP-ir and nNOS-ir neurons was not significantly different between GTN-treated and control animals.…”

Section: Cgrp Immunoreactive Neuronsmentioning

confidence: 89%

“…The average number of nNOS-ir neurons per slice was 3.6 AE 0.8 in the saline-treated animals, and 8.0 AE 0.8 in the GTN-treated group (p ¼ .028, Figure 2B). After infusion of GTN an increase in the number of nNOS positive neurons was observed in the V1 division (ANOVA F (1,8) …”

Section: Nnos Immunoreactive Neuronsmentioning

confidence: 99%

Increase in CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion after infusion of an NO donor

et al. 2010

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Background: Nitrovasodilators, such as glyceroltrinitrate (GTN), which produce nitric oxide (NO) in the organism, are known to cause delayed headaches in migraineurs, accompanied by increased plasma levels of calcitonin gene-related peptide (CGRP) in the cranial venous outflow. Increases in plasma CGRP and NO metabolites have also been found in spontaneous migraine attacks. In a rat model of meningeal nociception, infusion of NO donors induced activity of neurons in the spinal trigeminal nucleus. Methods: Isoflurane-anaesthetised rats were intravenously infused with GTN (250 mg/kg) or saline for two hours and fixed by perfusion after a further four hours. Cryosections of dissected trigeminal ganglia were immunostained for detection of CGRP and neuronal NO synthase (nNOS). The ganglion neurons showing immunofluorescence for either of these proteins were counted. Results: The proportions of CGRP-and nNOS-as well as double-immunopositive neurons were increased after GTN infusion compared to saline treatment in all parts of the trigeminal ganglion (CGRP) or restricted to the ophthalmic region (nNOS). The size of immunopositive neurons was not significantly different compared to controls. Conclusion: High levels of NO may induce the expression or availability of CGRP and nNOS. Similar changes may be involved in nitrovasodilator-induced and spontaneous headache attacks in migraineurs.

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“…One of the main side effects of NTG is migraine, which may develop within minutes, or up to four hours post-administration. 4) Systemic NTG activates nociceptive neurons in areas of the mouse brain. 5) In mice, a single injection of NTG induces acute mechanical, cold, and thermal hypersensitivity, which persists up to four hours post-injection.…”

mentioning

confidence: 99%

Differential Development of Facial and Hind Paw Allodynia in a Nitroglycerin-Induced Mouse Model of Chronic Migraine: Role of Capsaicin Sensitive Primary Afferents

Kim

Yeo

Yoon

et al. 2018

Biological & Pharmaceutical Bulletin

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Despite the relatively high prevalence of migraine or headache, the pathophysiological mechanisms triggering headache-associated peripheral hypersensitivities, are unknown. Since nitric oxide (NO) is well known as a causative factor in the pathogenesis of migraine or migraine-associated hypersensitivities, a mouse model has been established using systemic administration of the NO donor, nitroglycerin (NTG). Here we tried to investigate the time course development of facial or hindpaw hypersensitivity after repetitive NTG injection. NTG (10 mg/kg) was administrated to mice every other day for nine days. Two hours post-injection, NTG produced acute mechanical and heat hypersensitivity in the hind paws. By contrast, cold allodynia, but not mechanical hypersensitivity, occurred in the facial region. Moreover, this hindpaws mechanical hypersensitivity and the facial cold allodynia was progressive and long-lasting. We subsequently examined whether the depletion of capsaicin-sensitive primary afferents (CSPAs) with resiniferatoxin (RTX, 0.02 mg/kg) altered these peripheral hypersensitivities in NTG-treated mice. RTX pretreatment did not affect the NTG-induced mechanical allodynia in the hind paws nor the cold allodynia in the facial region, but it did inhibit the development of hind paw heat hyperalgesia. Similarly, NTG injection produced significant hindpaw mechanical allodynia or facial cold allodynia, but not heat hyperalgesia in transient receptor potential type V1 (TRPV1) knockout mice. These findings demonstrate that different peripheral hypersensitivities develop in the face versus hindpaw regions in a mouse model of repetitive NTG-induced migraine, and that these hindpaw mechanical hypersensitivity and facial cold allodynia are not mediated by the activation of CSPAs.Key words allodynia; nitroglycerin; migraine; resiniferatoxin; transient receptor potential type V1 (TRPV1) Migraine, a multifactorial primary headache disorder, is characterized by one-sided, severe, and pulsatile headaches. 1) During the headache phase, stimuli that are generally innocuous, such as ambient light or sound, can be unpleasant during headache. Most patients with migraines experience increased cutaneous sensitivity to non-noxious mechanical, cold, and thermal stimulation of the skin of the cephalic or non-cephalic regions of the body. 2) While central sensitization could contribute to the mechanisms underlying this cutaneous hypersensitivity, 2,3) the exact mechanisms are poorly understood.Nitroglycerin (NTG), a nitric oxide (NO) donor and effective vasodilator, is generally used to treat patients with angina. One of the main side effects of NTG is migraine, which may develop within minutes, or up to four hours post-administration. 4) Systemic NTG activates nociceptive neurons in areas of the mouse brain. 5) In mice, a single injection of NTG induces acute mechanical, cold, and thermal hypersensitivity, which persists up to four hours post-injection. 3,6) Recently Pradhan et al. reported that repetitive injections of NTG induced chron...

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Glyceryl Trinitrate Induces Attacks of Migraine Without Aura in Sufferers of Migraine with Aura

Cited by 177 publications

References 31 publications

Nitric Oxide-Related Drug Targets in Headache

Nitric Oxide-Related Drug Targets in Headache

Increase in CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion after infusion of an NO donor

Differential Development of Facial and Hind Paw Allodynia in a Nitroglycerin-Induced Mouse Model of Chronic Migraine: Role of Capsaicin Sensitive Primary Afferents

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