Animal Model of Chronic Migraine‐Associated Pain

Moye, Laura S.; Pradhan, Amynah

doi:10.1002/cpns.33

Cited by 46 publications

(43 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies indicate that NTG administration in rodents is a predictive model of migraine in humans [ 24 , 34 , 35 ]. In this study we aimed at developing and testing a chronic migraine-like model in rats, based on chronic and intermittent administration of NTG.…”

Section: Discussionmentioning

confidence: 99%

Chronic and intermittent administration of systemic nitroglycerin in the rat induces an increase in the gene expression of CGRP in central areas: potential contribution to pain processing

Greco¹,

Demartini²,

Zanaboni

et al. 2018

J Headache Pain

View full text Add to dashboard Cite

BackgroundCalcitonin gene related peptide (CGRP) is a key neuropeptide involved in the activation of the trigeminovascular system and it is likely related to migraine chronification. Here, we investigated the role of CGRP in an animal model that mimics the chronic migraine condition via repeated and intermittent nitroglycerin (NTG) administration. We also evaluated the modulatory effect of topiramate on this experimental paradigm. Male Sprague-Dawley rats were injected with NTG (5 mg/kg, i.p.) or vehicle, every 2 days over a 9-day period (5 total injections). A group of animals was injected with topiramate (30 mg/kg, i.p.) or saline every day for 9 days. Twenty-four hours after the last administration of NTG or vehicle, animals underwent tail flick test and orofacial Von Frey test. Rats were subsequently sacrificed to evaluate c-Fos and CGRP gene expression in medulla-pons region, cervical spinal cord and trigeminal ganglia.ResultsNTG administration induced spinal hyperalgesia and orofacial allodynia, together with a significant increase in the expression of CGRP and c-Fos genes in trigeminal ganglia and central areas. Topiramate treatment prevented NTG-induced changes by reversing NTG-induced hyperalgesia and allodynia, and inhibiting CGRP and c-Fos gene expression in all areas evaluated.ConclusionsThese findings point to the role of CGRP in the processes underlying migraine chronification and suggest a possible interaction with gamma-aminobutyrate (GABA) and glutamate transmission to induce/maintain central sensitization and to contribute to the dysregulation of descending pain system involved in chronic migraine.

show abstract

Section: Discussionmentioning

confidence: 99%

Chronic and intermittent administration of systemic nitroglycerin in the rat induces an increase in the gene expression of CGRP in central areas: potential contribution to pain processing

Greco¹,

Demartini²,

Zanaboni

et al. 2018

J Headache Pain

View full text Add to dashboard Cite

show abstract

“…In humans with migraine but not control subjects, NTG causes a delayed migraine (without aura) indistinguishable from spontaneous attacks ( Iversen, 1995 ; Tassorelli et al, 1999 ). NTG testing is thus used as a preclinical model for migraine without aura ( Bates et al, 2010 ; Greco et al, 2014 ; Pradhan et al, 2014 ; Kaufmann et al, 2016 ; Moye and Pradhan, 2017 ). CSD is the physiological substrate of the migraine aura in humans, and thus is used in preclinical models of migraine with aura ( Ayata et al, 2006 ; Chen et al, 2006 ; Brennan et al, 2007 ; Theriot et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

The Effects of Chronic Stress on Migraine Relevant Phenotypes in Male Mice

Kaufmann

Brennan

2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Migraine is a disabling neurological disorder affecting 12% of the world’s population. Stress is a major reported trigger and exacerbator of migraine. We evaluated the effects of two chronic stress paradigms on migraine relevant phenotypes in male C57Bl/6 mice.Methods: Fifty six mice were used in a 14 day social defeat stress (SDS) and twenty three mice were used in a 40 day chronic variable stress (CVS) paradigm. Anxiety measures were evaluated using the open field and elevated plus maze (EPM) tests. Migraine relevant phenotypes were evaluated using the nitroglycerin (NTG) and cortical spreading depression (CSD) models.Results: Stress sensitive SDS mice and chronically stressed CVS mice showed decreased exploration in the open field and reduced time spent in the open arms of the EPM compared to controls. Stress sensitive and resilient SDS mice had increased serum corticosterone levels, and stressed mice in the CVS paradigm had decreased weight gain compared to controls, providing combined behavioral and physiological evidence of a stress response. In the CVS paradigm but not the SDS paradigm, the stressed group showed a significant decrease in baseline mechanical withdrawal threshold compared to controls. All groups showed a significant reduction in withdrawal threshold after treatment with NTG, but the reduction was not larger in SDS or CVS than in controls. Interestingly, stress resilient SDS mice showed a rapid recovery from NTG effects that was not seen in other groups. No difference in CSD frequency or velocity was seen between stress and control mice in either stress paradigms.Conclusion: We observed distinct effects of stress on generalized pain response, migraine relevant pain, and migraine relevant excitability. CVS but not SDS was associated with a reduced mechanical withdrawal threshold, consistent with a generalized pain response to chronic stress. Neither SDS nor CVS exacerbated phenotypes considered specifically relevant to migraine - withdrawal to NTG, and susceptibility to CSD. However, the significantly reduced response of stress resilient mice to the NTG stimulus may represent a specific migraine-resistant phenotype.

show abstract

“…In our study, we developed a mouse CM model with repeated NTG injections that was first described by Pradhan et al [9]. In his research, chronic intermittent treatment with NTG not only produced acute mechanical hypersensitivity of the hind paw after each injection but also induced long-lasting basal hyperalgesia, which was alleviated by the migraine-preventive treatment of topiramate.…”

Section: Animal Model Of Chronic Migrainementioning

confidence: 94%

“…The vehicle control was 0.9% saline. There was no significant difference in mechanical thresholds between the 0.9% saline solution and the solution in which NTG was dissolved (6% propylene glycol, 6% alcohol, 0.9% saline) [9]. The animals received intraperitoneal (i.p.)…”

Section: Animal Modelling and Experimental Designmentioning

confidence: 99%

Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model

Long

Pan

et al. 2020

J Headache Pain

View full text Add to dashboard Cite

Background: According to our previous study, microglia P2X4 receptors (P2X4Rs) play a pivotal role in the central sensitization of chronic migraine (CM). However, the molecular mechanism that underlies the crosstalk between microglia P2X4Rs and neurons of the trigeminal nucleus caudalis (TNC) is not fully understood. Therefore, the aim of this study is to examine the exact P2X4Rs signalling pathway in the development of central sensitization in a CM animal model. Methods: We used an animal model with recurrent intermittent administration of nitroglycerin (NTG), which closely mimics CM. NTG-induced basal mechanical and thermal hypersensitivity were evaluated using a von Frey filament test and an increasing-temperature hot plate apparatus (IITC). We detected P2X4Rs, brain-derived neurotrophic factor (BDNF) and phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK) expression profiles in the TNC. We investigated the effects of a P2X4R inhibitor (5-BDBD) and an agonist (IVM) on NTG-induced hyperalgesia and neurochemical changes as well as on the expression of p-p38-MAPK and BDNF. We also detected the effects of a tropomyosin-related kinase B (TrkB) inhibitor (ANA-12) on the CM animal model in vivo. Then, we evaluated the effect of 5-BDBD and SB203580 (a p38-MAPK inhibitors) on the release and synthesis of BDNF in BV2 microglia cells treated with 50 μM adenosine triphosphate (ATP). Results: Chronic intermittent administration of NTG resulted in chronic mechanical and thermal hyperalgesia, accompanied by the upregulation of P2X4Rs and BDNF expression. 5-BDBD or ANA-12 prevented hyperalgesia induced by NTG, which was associated with a significant inhibition of the NTG-induced increase in phosphorylated extracellular regulated protein kinases (p-ERK) and calcitonin gene related peptide (CGRP) release in the TNC. Repeated administration of IVM produced sustained hyperalgesia and significantly increased the levels of pERK and CGRP release in the TNC. Activating P2X4Rs with ATP triggered BDNF release and increased BDNF synthesis in BV2 microglia, and these results were then reduced by 5-BDBD or SB203580. Conclusions: Our results indicated that the P2X4R contributes to the central sensitization of CM by releasing BDNF and promoting TNC neuronal hyper-excitability. Blocking microglia P2X4R-BDNF signalling may have an effect on the prevention of migraine chronification.

show abstract

Animal Model of Chronic Migraine‐Associated Pain

Cited by 46 publications

References 30 publications

Chronic and intermittent administration of systemic nitroglycerin in the rat induces an increase in the gene expression of CGRP in central areas: potential contribution to pain processing

Chronic and intermittent administration of systemic nitroglycerin in the rat induces an increase in the gene expression of CGRP in central areas: potential contribution to pain processing

The Effects of Chronic Stress on Migraine Relevant Phenotypes in Male Mice

Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model

Contact Info

Product

Resources

About