Effect of Sex and Estrogens on Neuronal Activation in an Animal Model of Migraine

Greco, Rosaria; Tassorelli, Cristina; Mangione, Antonina Stefania; Smeraldi, Antonella; Allena, Marta; Sandrini, Giorgio; Nappi, Giuseppe; Nappi, Rossella E.

doi:10.1111/j.1526-4610.2012.02249.x

Cited by 46 publications

(42 citation statements)

References 48 publications

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“…It has previously been reported that systemic GTN administration produces a greater mechanical hyperalgesia in female mice (Pradhan et al, 2014) and a greater increase expression of FOS protein (a marker of neuronal activity) in brain nuclei associated with pain processing of females rats (Greco et al, 2013). Although there is a markedly higher prevalence of migraine in women and a marked reduction in pain severity following depletion of female sex steroids (Brandes, 2006), to our knowledge sex differences in migraine severity induced by GTN infusion in human studies has not been evaluated.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat

2016

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Nitroglycerin (glycerol trinitrate, GTN) induces headache in migraineurs, an effect that has been used both diagnostically and in the study of the pathophysiology of this neurovascular pain syndrome. An important feature of this headache is a delay from the administration of GTN to headache onset that, because of GTN’s very rapid metabolism, cannot be due to its pharmacokinetic profile. It has recently been suggested that activation of perivascular mast cells, which has been implicated in the pathophysiology of migraine, may contribute to this delay. We reported that hyperalgesia induced by intradermal GTN has a delay to onset of ~30 min in male and ~45 min in female rats. This hyperalgesia was greater in females, was prevented by pretreatment with the anti-migraine drug, sumatriptan, as well as by chronic pretreatment with the mast cell degranulator, compound 48/80. The acute administration of GTN and compound 48/80 both induced hyperalgesia that was prevented by pretreatment with octoxynol-9, which attenuates endothelial function, suggesting that GTN and mast cell-mediated hyperalgesia are endothelial cell-dependent. Furthermore, A-317491, a P2X3 antagonist, which inhibits endothelial cell-dependent hyperalgesia, also prevents GTN and mast cell-mediated hyperalgesia. We conclude that delayed onset mechanical hyperalgesia induced by GTN is mediated by activation of mast cells, which in turn release mediators that stimulate endothelial cells to release ATP, to act on P2X3, a ligand-gated ion channel, in perivascular nociceptors. A role of the mast and endothelial cell in GTN-induced hyperalgesia suggest potential novel risk factors and targets for the treatment of migraine.

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Section: Discussionmentioning

confidence: 99%

Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat

2016

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“…Additionally, there is a need for basic science in translational medicine, as translating findings from animal models to the human condition has been a challenge. In the migraine field, there are a number of “animal models”, however, most use male animals (e.g., (113, 186)), which confounds sex differences in migraine. Another approach to study the influence of hormones is to investigate short term and long term effects of contraceptive use on migraine, as there is compelling evidence that oral contraceptive alter brain function (187, 188) and structure in regions such as the prefrontal cortex, pre- and post-central gyri, parahippocampal and fusiform gyri, and temporal regions (43).…”

Section: Future Directionsmentioning

confidence: 99%

“…It is postulated that estrogen and estrogen receptors in the sensory pathways may alter sensitivity to nociception in these neurons (186). …”

Section: Figurementioning

confidence: 99%

Sex and the migraine brain

Borsook

Erpelding

Lebel

et al. 2014

Neurobiology of Disease

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The brain responds differently to environmental and internal signals that relates to the stage of development of neural systems. While genetic and epigenetic factors contribute to a premorbid state, hormonal fluctuations in women may alter the set point of migraine. The cyclic surges of gonadal hormones may directly alter neuronal, glial and astrocyte function throughout the brain. Estrogen is mainly excitatory and progesterone inhibitory on brain neuronal systems. These changes contribute to the allostatic load of the migraine condition that most notably starts at puberty in girls.

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“…However, after puberty, migraine prevalence in women is more than threefold compared with that of men [116,120]. Migraine frequency and intensity have been shown to be influenced by hormonal events such as menstruation, pregnancy and menopause [121][122][123][124][125][126][127][128]. Steroid hormones, estrogen and progesterone, modulators of the menstrual cycle, have thus been considered a triggering factor involved in the onset of many migraine attacks [129].…”

Section: Hormone Receptor Genesmentioning

confidence: 98%

Emerging Genomic Biomarkers In Migraine

Menon

Griffiths

2012

Future Neurol.

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Migraine is a debilitating neurovascular condition classified as either migraine with aura or migraine without aura. A significant genetic basis has been implicated in migraine and has probed the role of neurotransmitters, hormones and vascular genes in this disorder. The aim of this review is to highlight the recent genetic discoveries contributing to our understanding of the complex pathogenesis of migraine. The current review will discuss the role of neurotransmitter-related genes in migraine, including the recently identified TRESK and variants of the KCNN3 gene, as well as outlining studies investigating hormone receptor genes, such as ESR1 and PGR, and vascular-related genes, including the MTHFR and NOTCH 3 genes.

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Effect of Sex and Estrogens on Neuronal Activation in an Animal Model of Migraine

Abstract: These data provide a support for the existence of a sexual dimorphism in NTG-induced neuronal activation, and they prompt a specific model for evaluating and modulating the influence of estrogens upon the cerebral structures implicated in the pathophysiology of migraine.

Cited by 46 publications

References 48 publications

Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat

Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat

Sex and the migraine brain

Emerging Genomic Biomarkers In Migraine

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