The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification

Harris, Hannah M.; Carpenter, Jessica M.; Black, Jonathan R.; Smitherman, Todd A.; Sufka, Kenneth J.

doi:10.1016/j.jneumeth.2017.04.010

Cited by 50 publications

(42 citation statements)

References 26 publications

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“…Furthermore, trigeminal overexpression of MT2 in rats also induced a chronic facial allodynia. This facial allodynia can be a facial hypersensitivity without migraine; however, orbitofacial allodynia is clearly accepted as a reflection of the activity of TG neurons and therefore relevant to migraine (Pradhan et al, 2014;Kopruszinski et al, 2017;Harris et al, 2017). Nevertheless, inhibition of TREK1/TREK2 by TRESK-MT2 fragments will depend on its physiological expression and remains to be demonstrated without overexpression.…”

Section: Discussionmentioning

confidence: 99%

“…We conducted behavioral experiments in rats in which MT2 was virally overexpressed within the trigeminal ganglia. Rats allowed to test the mechanical pain threshold on the face, which is directly linked to TG excitability, constituting a relatively direct, reliable, and quantifiable marker of migraine disorder in clinical contexts as well as in NO-induced migraine (Pradhan et al, 2014;Kopruszinski et al, 2017;Harris et al, 2017). As shown in Figure 7F, MT2 expression in TG ganglia (Figure S9) significantly increased the facial mechanical threshold (3.3 ± 0.4 g versus 7.7 ± 0.4 g; p < 0.001).…”

Section: Tresk-mt Mutation Induces the Translation Of A Second Proteimentioning

confidence: 99%

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Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Royal

Andrés‐Bilbé

Prado

et al. 2019

Neuron

113

131

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Section: Discussionmentioning

confidence: 99%

Section: Tresk-mt Mutation Induces the Translation Of A Second Proteimentioning

confidence: 99%

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Royal

Andrés‐Bilbé

Prado

et al. 2019

Neuron

113

131

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“…This chronic basal hyperalgesia persists for days following cessation of NTG administration. Further, repeated administration of NTG has also been shown to produce photophobia, hypoactivity, and facial grimace behaviors [22]. Therefore, this is a reliable animal model for studying chronic migraine-associated pain.…”

Section: Discussionmentioning

confidence: 99%

Microglia P2X4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation

Long

Pan

et al. 2018

J Neuroinflammation

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BackgroundThe mechanism underlying migraine chronification remains unclear. Central sensitization may account for this progression. The microglia P2X4 receptor (P2X4R) plays a pivotal role in the central sensitization of inflammatory and neuropathic pain, but there is no information about P2X4R in migraine. Therefore, the aim of this study was to identify the precise role of microglia P2X4R in chronic migraine (CM).MethodsWe used an animal model with recurrent intermittent administration of nitroglycerin (NTG), which closely mimics CM. NTG-induced basal and acute mechanical hypersensitivity were evaluated using the von Frey filament test. Then, we detected Iba1 immunoreactivity (Iba1-IR) and P2X4R expression in the trigeminal nucleus caudalis (TNC). To understand the effect of microglia and P2X4R on central sensitization of CM, we examined whether minocycline, an inhibitor of microglia activation, and 5-BDBD, a P2X4R antagonist, altered NTG-induced mechanical hyperalgesia. In addition, we also evaluated the effect of 5-BDBD on c-Fos and calcitonin gene-related peptide (CGRP) expression within the TNC.ResultsChronic intermittent administration of NTG resulted in acute and chronic basal mechanical hyperalgesia, accompanied with microglia activation and upregulation of P2X4R expression. Minocycline significantly decreased basal pain hypersensitivity but did not alter acute NTG-induced hyperalgesia. Minocycline also reduced microglia activation. 5-BDBD completely blocked the basal and acute hyperalgesia induced by NTG. This effect was associated with a significant inhibition of the NTG-induced increase in c-Fos protein and CGRP release in the TNC.ConclusionsOur results indicate that blocking microglia activation may have an effect on the prevention of migraine chronification. Moreover, we speculate that the P2X4R may be implicated in the microglia-neuronal signal in the TNC, which contributes to the central sensitization of CM.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1285-3) contains supplementary material, which is available to authorized users.

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“…CADASIL and FASP animals received serial NTG injections on Days 0, 2, 4, 6, and 8 (the day of the gastrointestinal motility procedure), similar to prior reports in mice 43 and rats, 44,45 with the intent to maximize the effects of pretreatment with NTG. CADASIL and FASP animals received serial NTG injections on Days 0, 2, 4, 6, and 8 (the day of the gastrointestinal motility procedure), similar to prior reports in mice 43 and rats, 44,45 with the intent to maximize the effects of pretreatment with NTG.…”

Section: Methodsmentioning

confidence: 99%

“…Animals that underwent pretreatment were administered 10 mg/kg NTG, which came diluted in 5% dextrose (100 mg/250 mL) (Baxter Healthcare Corp., Deerfield, IL), or corresponding vehicle (5% dextrose) subcutaneously at the nape of the neck by tenting the skin. CADASIL and FASP animals received serial NTG injections on Days 0, 2, 4, 6, and 8 (the day of the gastrointestinal motility procedure), similar to prior reports in mice 43 and rats, 44,45 with the intent to maximize the effects of pretreatment with NTG. FHM1 animals were injected only once (to limit the handling of the animals) on the day of the procedure given the higher risk for mortality in homozygous CACNA1A-S218L mice.…”

Section: Methodsmentioning

confidence: 99%

No Gastrointestinal Dysmotility in Transgenic Mouse Models of Migraine

et al. 2019

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Objective.-To determine whether transgenic mouse models of migraine exhibit upper gastrointestinal dysmotility comparable to those observed in migraine patients.Background.-There is considerable evidence supporting the comorbidity of gastrointestinal dysmotility and migraine. Gastrointestinal motility, however, has never been investigated in transgenic mouse models of migraine.Methods.-Three transgenic mouse strains that express pathogenic gene mutations linked to monogenic migraine-relevant phenotypes were studied: CADASIL (Notch3-Tg88), FASP (CSNK1D-T44A), and FHM1 (CACNA1A-S218L). Upper gastrointestinal motility was quantified by measuring gastric emptying and small intestinal transit in mutant and control animals. Gastrointestinal motility was measured at baseline and after pretreatment with 10 mg/kg nitroglycerin (NTG).Results. -No significant differences were observed for gastric emptying or small intestinal transit at baseline for any of the 3 transgenic strains when compared to appropriate controls or after pretreatment with NTG when compared to vehicle.Conclusions.-We detected no evidence of upper gastrointestinal dysmotility in mice that express mutations in genes linked to monogenic migraine-relevant phenotypes. Future studies seeking to understand why humans with migraine experience delayed gastric emptying may benefit from pursuing other modifiers of gastrointestinal motility, such as epigenetic or microbiome-related factors.Abbreviations: CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, FASP familial advanced sleep phase, FHM familial hemiplegic migraine, IBS irritable bowel syndrome, IG idiopathic gastroparesis, NTG nitroglycerin (Headache 2020;60:396-404) Headache

show abstract

The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification

Cited by 50 publications

References 26 publications

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Microglia P2X4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation

No Gastrointestinal Dysmotility in Transgenic Mouse Models of Migraine

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