Nitroglycerin induces migraine headache and central sensitization phenomena in patients with migraine without aura: a study of laser evoked potentials

doi:10.1016/j.neulet.2004.04.029

Neuroscience Letters

Volume 363, Issue 3, 17 June 2004, Pages 272-275

https://doi.org/10.1016/j.neulet.2004.04.029 Get rights and content

Abstract

In migraineurs nitroglycerin (NTG) induces severe delayed headache, resembling spontaneous migraine attacks. The aim of the present study was to evaluate NTG laser evoked potentials (LEP) features amplitude and pain sensation to laser stimuli during NTG-induced headache. Nine patients were selected. Headache was induced by oral administration of 0.6 mg of NTG; signals were recorded through disk electrodes placed at the vertex and referred to linked earlobes. CO₂-LEPs delivered by stimulation of the dorsum of both hands and the right and left supraorbital zones were evaluated after the onset of moderate or severe headache resembling spontaneous migraine and at least 72 h after the end of the headache phase. Patients exhibited a significant heat pain threshold reduction and an LEPs amplitude increment during headache when both the supraorbital zones were stimulated. NTG appeared to support a reliable experimental model of migraine, based on the neuronal effects on the integrative-nociceptive structures. The LEPs facilitation during NTG-induced headache may be subtended by a hyperactivity of nociceptive cortex as well as by a failure of pain-inhibitory control.

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Since the first electroencephalographic recordings obtained by Golla and Winter in 1959, researchers have used a variety of neurophysiological techniques to determine the mechanisms underlying recurrent migraine attacks. Neurophysiological methods have shown that the brain during the interictal phase of an episodic migraine is characterized by a general hyperresponsiveness to sensory stimuli, a malfunction of the monoaminergic brainstem circuits, and by functional alterations of the thalamus and thalamocortical loop. All of these alterations vary plastically during the phases of the migraine cycle and interictally with the days following the attack. Both episodic migraineurs recorded during an attack and chronic migraineurs are characterized by a general increase in the cortical amplitude response to peripheral sensory stimuli; this is an electrophysiological hallmark of a central sensitization process that is further reinforced through medication overuse. Considering the large-scale functional involvement and the main roles played by the brainstem-thalamo-cortical network in selection, elaboration, and learning of relevant sensory information, future research should move from searching for one specific primary site of dysfunction at the macroscopic level, to the chronic, probably genetically determined, molecular dysfunctions at the synaptic level, responsible for short- and long-term learning mechanisms.
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DCXF extract was prepared by mixing Chuanxiong Rhizoma and Gastrodiae Rhizoma at a mass ratio of 4:1 (w/w). After extraction, the extract was filtered prior to high performance liquid chromatography (HPLC) analysis. Nitroglycerin (NTG) was used to establish a mouse migraine model, and a behaviour study was conducted by hot plate test. In addition, proteomics and bioinformatics studies were conducted to investigate the mechanisms of DCXF-mediating anti-migraine treatment.
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In patients who suffer from migraine without aura, orally administered NTG exhibited a significant heat pain threshold reduction. The patients experienced a slight headache immediately after NTG intake and a moderate or severe subsequent headache accompanied by non-headache symptoms like nausea, vomiting, and photophobia [11]. In line with previous studies, our data shows that female rats manifest more severe NTG-induced migraine symptoms.
Stress is known to cause migraine. This study investigates the effects of neonatal maternal deprivation (MD) and chronic unpredictable stress (CUS) on migraine in rats.
Seventy rats were randomly divided into ten groups (five groups of each sex, and seven rats/group). The groups included: untreated intact, nitroglycerin (NTG) only, NTG + MD, NTG + CUS (10 weeks after birth), and NTG + MD + CUS. For the induction of MD, pups were separated from their mothers from postnatal day 2 to day 14. The CUS was conducted by daily exposure to different stressors for 2 weeks. For the induction of migraine after stress, NTG (5 mg/kg/IP) was administered every second day for 9 days. Afterward, NTG-related symptoms, including climbing behavior, facial rubbing, body grooming, freezing behavior, and head-scratching, were recorded for 90 min. Statistical differences between the groups were analyzed by one-way and two-way ANOVA followed by the Newman–Keuls test.
Migraine symptoms, including increased head-scratching, facial rubbing, and decreased climbing behavior, were more significant in females than in males. Head scratching and facial rubbing increased in stressed females, but not in males as compared to NTG-treated rats. Body grooming was significantly decreased in MD males compared to the NTG group. The effects of NTG in MD + CUS on the rats did not differ from those in the MD or CUS groups.
MD and CUS had a sex-related aggravating effect on the development of migraine, while the combination of MD and CUS had no additive migraine-aggravating effect.
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Nitroglycerin (NTG) treatment in rodents has been used to model migraine after it was found clinically that a large percentage of patients being treated with nitrile drugs experience headache. The NTG model shares important features with what is seen in human migraine patients such as shared pain behaviors, central sensitization, and cortical spreading depression (de Tommaso et al. 2004; Knapp et al. 2017; Long et al. 2020). Rodent models employing single and chronic administration of NTG show both facial and hindpaw hypersensitivities as well as photophobia (Anapindi et al. 2019; Bates et al. 2010; Casili et al. 2020; Farajdokht et al. 2017; Farkas et al. 2016; Guo et al. 2021; Moye et al. 2019; Pan et al. 2022; Shu et al. 2020; Tang et al. 2018; Zhang et al. 2020a).
Migraine is a leading cause of disability among the adult population and is a significant burden on the economies of the world. Studies into the underlying causes of migraine have spanned centuries but its underlying mechanisms are still not fully understood. In recent years, accumulating evidence implicates that microbiota-mediated gut-brain crosstalk may contribute to the pathogenesis of migraine. This review provides a brief account of the history of migraine theories and summarizes the recent studies showing how gut microbiota is involved in the pathophysiology of migraine. Future research perspectives for better understanding the role of the gut microbiota in migraine are also discussed.
Nitric oxide role in anxiety-like behavior, memory and cognitive impairments in animal model of chronic migraine
2020, Heliyon
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NO is an important neurotransmitter in pain pathways and it is considered to play a fundamental role in migraine pathophysiology [7]. It has been demonstrated that the administration of nitroglycerin (NTG) as a nitric oxide donor induces a headache in healthy subjects and more severe delayed headache in migraineurs [8]. A lower cognitive performance has been reported in painful conditions [9].
The occurrence of cognitive dysfunctions and anxiety and mood disorders has been shown to be higher in migraine patients. Nitric Oxide (NO) is a significant neurotransmitter in the pathophysiology of migraine, anxiety and neurodegenerative disorders. Therefore, the present study was conducted to evaluate the role of NO system in migraine-induced memory impairment and anxiety like behaviors. Nitroglycerin (NTG) was administered to the animals as an animal model of migraine and pretreatment with L-Arginine, L-NAME and saline were implemented to evaluate the role of NO system in possible cognitive impairments in animal model of migraine. Avoidance learning and memory performance, object recognition memory, anxiety-like behavior and motor activity were assessed using a shuttle box apparatus, novel object recognition, elevated plus-maze, and open field tests respectively. The data showed that the injection of nitroglycerin disturbs learning and memory and elicit anxiety like behavior in the animals. L-NAME administration suppressed the observed effect of nitroglycerin on memory and anxiety. Overall, the results indicated that nitric oxide system is implicated in memory impairments and anxiety like behavior in an animal model of migraine.
Activation orexin 1 receptors in the ventrolateral periaqueductal gray matter attenuate nitroglycerin-induced migraine attacks and calcitonin gene related peptide up-regulation in trigeminal nucleus caudalis of rats
2020, Neuropharmacology
Citation Excerpt :
The above pathway may promote the release of pro-nociceptive and pro-inflammatory mediators in both spinal and trigeminal nerves leading to peripheral and central sensitization. Consequently, an enhanced sensitivity for pain can be seen in migraine sufferers (de Tommaso et al., 2002, 2004). Orexin-A (OrxA) is produced by a small number of neurons in the lateral and posterior hypothalamic regions.
This study aims to explore whether orexin 1 receptors (Orx1R) in the ventrolateral periaqueductal gray matter (vlPAG) play a role in the modulation of migraine headaches in adult male Wistar rats. To model chronic migraine-associated pain, nitroglycerin (NTG) (5 mg/kg/IP) was administered to test subjects every second day for 9 days. After the last NTG injection, rats were randomly separated into the following groups (n = 6): orexin-A (OrxA) groups that received intra-vlPAG OrxA (25, 50, and 100 pM), an Orx1R antagonist group, a SB-334867 (20 μM) group; and a SB-334867 (20 μM) + OrxA (100 pM) group. After 10 min, migraine-associated behavioral symptoms were recorded in all animals for up to 90 min. Light-dark chamber and hot plate tests were used for assessing light aversion and thermal hyperalgesia, respectively. Calcitonin gene-related peptide (CGRP)-positive cells were detected in the trigeminal nucleus caudalis (Vc) by immunofluorescence microscopy. NTG caused significant freezing behavior, which was prevented by all OrxA doses. Moreover, OrxA (100 pM) could obstruct NTG-induced increases in facial rubbing and decreases in climbing and body grooming. Furthermore, NTG-induced light aversion and thermal hyperalgesia were attenuated by OrxA at doses of 50 and 100 pM. The effects of OrxA were significantly blocked by SB-334867 (20 μM). Besides, OrxA (100 pM) decreased NTG-induced CGRP upregulation. The data revealed that the activation of Orx1Rs in the vlPAG is effective in relieving NTG-induced migraine symptoms mainly by the downregulation of CGRP in the Vc of rats.

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Nitroglycerin induces migraine headache and central sensitization phenomena in patients with migraine without aura: a study of laser evoked potentials

Abstract

Neurosci. Lett.

Brain Res.

Eur. J. Pharmacol.

Prog. Neurobiol.

Clin. Neurophysiol.

Electroenceph. clin. Neurophysiol.

Clin. Neurophysiol.