Experimental models of migraine

doi:10.1016/S0072-9752(10)97008-5

Handbook of Clinical Neurology

Volume 97, 2010, Pages 109-123

https://doi.org/10.1016/S0072-9752(10)97008-5 Get rights and content

Abstract

In vitro studies on animal and human cephalic vessels allow the measurement of second messengers or intracellular calcium concentrations and the evaluation of the role of endogenous neuropeptides in perivascular nerve endings involved in migraine pathophysiology. In addition, in vitro human models allow the assessment of receptorial cranial selectivity and the collection of reliable information regarding the behavior of these vessels in migraine headache. The availability of animal models of migraine has favoured impressive advances in understanding the mechanisms and mediators underlying migraine attacks, as well as the development of new and more specific therapeutic agents. The trigeminovascular system (TVS) has emerged as a critical efferent component, and the mediators of its activity have been identified and characterized, as have some of the receptors involved. The similarity of the trigeminal innervation across species has made it possible to draw conclusions on the neurophysiological responses to electrical or chemical stimulation of the trigeminal fibers. Studies involving substances known to induce migraine-like attacks, i.e., nitric oxide (NO) donors, have provided interesting insights into the central nuclei probably involved in the initiation and repetition of migraine attacks. The neuronal and vascular effects of such substances might yield an increasing body of evidence for a better understanding of the pathophysiology of migraine attacks.

Introduction

In the past two decades, the availability of animal models of migraine has allowed impressive advances in understanding the mechanisms and mediators underlying migraine attacks, as well as the development of new and more specific therapeutic agents. The trigeminovascular system (TVS) has emerged as a critical efferent component, and the mediators of its activity have been identified and characterized, as have some of the receptors involved. Studies involving substances known to induce migraine-like attacks have provided interesting insights into the central nuclei probably involved in the initiation and recurrence of migraine attacks. Furthermore, new molecules, potentially effective in migraine treatment, have been screened and tested in the different experimental models so far available and, having given satisfactory results, are now in the pipeline to become commercially available antimigraine drugs (Figure 8.1).

Over the years, animal models of several types have been devised, proposed, tested, and used. These models are listed in a schematic classification in Table 8.1 (for review see also Bergerot et al., 2006).

Section snippets

In vitro

Isolated cranial (meningeal, temporal, basilar) and coronary arteries of animals are used as in vitro models of migraine to characterize the receptors in these blood vessels and to study the effects of potential antimigraine molecules. However, it should be borne in mind that a species that is a good model for a certain class of drugs may be less suitable for studying other receptor systems. Blood vessels can be studied using anatomical, physiological, and pharmacological methods and studies

Neurovascular Models

The neurogenic model of migraine implies that any stimulus that depolarizes trigeminal sensory fibers activates the TVS and induces blood flow changes in intra- and extracranial tissues receiving trigeminal innervation (Moskowitz, 1984). The trigeminal pain pathway, as related to migraine, is comprised of three main sites: (1) the trigeminal cells in the ganglion with their projections to the vessels (TVS) and to the brainstem; (2) the trigeminal nucleus caudalis (TNC) in the brainstem; and (3)

Genetic Factors and Migraine

Genetic factors play an important role in migraine pathophysiology (Kors et al., 2004), probably by lowering the threshold for migraine. Familial hemiplegic migraine (FHM) is an autosomal-dominant subtype of migraine with aura. Apart from the characteristic hemiparesis, typical attacks of FHM are identical to those of the common forms of migraine. This rare and severe form of migraine has been associated with three different mutations identified in three genes encoding subunits of a calcium

Acknowledgment

The authors are grateful to Dr Rosaria Greco for her support in the preparation of the manuscript.

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Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine
2021, Neurobiology of Disease
Citation Excerpt :
All experiments were conducted in a randomized manner by an experimenter who was blinded to treatments. In this study, two NTG-based animal models were used to mimic episodic and chronic migraine pain (Buzzi and Tassorelli, 2010; Pradhan et al., 2014; Demartini et al., 2019). NTG (Bioindustria L.I.M. Novi Ligure (AL), Italy) was prepared from a stock solution of 5.0 mg/1.5 ml dissolved in 27% alcohol and 73% propylene glycol.
Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia – an animal model of migraine - and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription.
The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways.
Nitroglycerin as a comparative experimental model of migraine pain: From animal to human and back
2019, Progress in Neurobiology
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Taken together these observations show a remarkable overlap of clinical, pharmacological and neuroimaging findings obtained during spontaneous migraines and NTG-induced headaches in migraineurs, which strengthens the adoption of NTG-induced headaches as an ideal tool for exploring the pathophysiology of primary headaches in controlled experimental settings. Developing animal models that have validity for a complex disorder like migraine presents formidable challenges, since the biological determinants of the clinical manifestations of the disorder have so far eluded discovery, despite the identification of several neurobiological abnormalities associated with the condition (Buzzi and Tassorelli, 2010). The observation regarding provocation of migraine-like attacks by NTG administration in humans prompted the possibility to model the same paradigm in laboratory animals in order to reproduce and investigate the mechanisms underlying migraine pain (Tassorelli and Joseph, 1995a, b; Tassorelli et al., 1999).
Migraine is a disease for which there is still no defined pathophysiological etiology and few translational models. The organic nitrate nitroglycerin has been in use as an experimental model of migraine in both human and animal studies for several years. The drug produces a number of effects within the head, that includes blood vessels, nerves and brain areas that may produce a response similar to a migraine attack in predisposed subjects. A better understanding of the nature of these changes and how well they parallel a true migraine attack would allow for a translational model to better understand some of the mechanisms involved in the generation of a migraine attack. The present review summarizes the known body of knowledge of nitroglycerin effects evaluated in humans and animals as it relates to potential mechanisms associated with migraine headaches.
Cerebrolysin attenuates hyperalgesia, photophobia, and neuroinflammation in a nitroglycerin-induced migraine model in rats
2018, Brain Research Bulletin
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Given the complexity of migraine, a proper animal modeling which mimics all the clinical features of this disorder in human is difficult. Systemic injection of NTG is a well-established model for chemical activation of the trigeminovascular system (TS) which has a good reproducibility and clinically relevance to human migraine (Buzzi and Tassorelli, 2010; Sufka et al., 2016; Markovics et al., 2012). Several studies have shown that acute or chronic NTG injection induces allodynic responses and light-aversive behaviors (Markovics et al., 2012; Farajdokht et al., 2016; Farajdokht et al., 2017a).
Chronic migraine dramatically affects the quality of life in the migraineurs. This study examined the effect of chronic cerebrolysin (CBL) treatment on the migraine-associated symptoms in a rat model of migraine. Experiments were carried out on 8 weeks, male Wistar rats. Chronic migraine was modeled by injection (10 mg/kg, i.p) of nitroglycerin (NTG) on days 3, 5, 7, and 9. CBL (2.5 and 5 ml/kg, i.p.) was injected every day for 10 days. Mechanical and thermal withdrawal thresholds of the hind paw were examined by von Frey hairs and hot plate, respectively. Head grooming behavior was evaluated one hour following injection of NTG. Light-aversive behaviors were determined in the modified elevated plus-maze (EPM) on even days and in the light/dark box on odd days. After behavioral experiments, blood concentrations of calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), tumor necrosis factor-a (TNF-α), and interleukin-1β (IL-1β) were assessed by rat specific enzyme-linked immunosorbent assay (ELISA) kits. Our results indicated that NTG significantly increased migraine-related behavioral and molecular symptoms in the animals, whereas CBL treatment markedly reduced mechanical and thermal hyperalgesia, head grooming, and light-aversive behaviors induced by NTG. Also, blood levels of CGRP, PACAP, and pro-inflammatory cytokines (TNF-α and IL-1β) significantly decreased by CBL administration. Chronic CBL treatment showed antinociceptive and light-aversive reducing effects in the NTG-induced animal model of chronic migraine and may represent a valuable therapy for those suffering from migraine.
The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification
2017, Journal of Neuroscience Methods
Rodent models typically use a single nitroglycerin injection to induce migraine, yet migraine in clinical populations presents as recurrent episodes. Further, these models quantify behavioral endpoints that do not align with the clinical features of episodic migraine or migraine chronification and therefore may limit translational relevance.
Rats received 5 nitroglycerin (10 mg/kg/2 ml), propylene glycol/ethanol vehicle, or saline injections every third day over 15 days. Behavioral endpoints were assessed 110 min post nitroglycerin administration and included time spent light/dark chambers for photophobia as well as activity, facial pain expressions, and tactile allodynia.
Animals administered nitroglycerin displayed photophobia, decreased activity, and increased facial pain expression. Similar alterations in photophobia and activity were seen in the vehicle treated animals, but these tended to diminish by the 4th or 5th injection. The presentation of spontaneous tactile allodynia was observed in the nitroglycerin group by the 5th episode.
Most NTG migraine models entail a single NTG administration and quantification of evoked allodynia. This paradigm employs recurring NTG episodes and clinically-relevant measures of photophobia, hypoactivity and facial grimace endpoints as well as introduces a novel arena apparatus to quantify spontaneous allodynia.
This repeated NTG procedure and endpoint measures aligns with the frequency and clinical presentation of episodic migraine and its chronification, respectively. Further, propylene glycol ethanol vehicle contributes to migraine endpoints.
Transcriptomic Changes in Rat Cortex and Brainstem After Cortical Spreading Depression With or Without Pretreatment With Migraine Prophylactic Drugs
2017, Journal of Pain
Migraine with aura is a subtype of migraine characterized by transient neurological disturbances that usually precede headache. Cortical spreading depression (CSD) is the likely pathophysiological correlate of the aura phase of migraine, found in common and rare forms of migraine, such as familial hemiplegic migraine. CSD is a depolarization wave that propagates across the cerebral gray matter transiently suppressing neuronal activity. Prophylactic treatments for migraine, such as topiramate or valproate, reduce the number of CSD events. We evaluated changes in gene expression in rat cortex and brainstem after inducing CSD in the cortex, with and without a prophylactic treatment with topiramate or valproate. CSD induction showed similar transcriptomic profiles with and without treatment in cortex, involving genes related to hormone stimulus, apoptosis, synaptic transmission, and interleukin signaling. In brainstem, CSD with and without treatment, although to a lesser extent, also induced gene expression changes involving genes related to apoptosis. Half of the genes altered in brainstem after CSD were also differentially expressed in the same direction in cortex. No differences in gene expression were identified after CSD as a consequence of the treatments, neither in cortex nor in brainstem.
Our results suggest that early after triggering the CSD, similar consequences are seen at the genetic level with or without prophylactic treatment. Gene expression changes induced by CSD in cortex and brainstem may help to better understand the underlying mechanisms and identify targets for therapeutic approaches.
Correlation between algogenic effects of calcitonin-gene-related peptide (CGRP) and activation of trigeminal vascular system, in an in vivo experimental model of nitroglycerin-induced sensitization
2014, European Journal of Pharmacology
Citation Excerpt :
Moreover NO induces an initial, transient phase of neuronal activation and then a delayed, long phase of high neuronal activity in the NTC of the rat, which is reminiscent of findings observed in clinical studies on migraineurs (Koulchitsky et al., 2004). Thus, the i.p. administration of nitroglycerin is currently considered as a reliable animal model of migraine (Buzzi and Tassorelli, 2010). The present study was addressed to investigate CGRP-evoked behavior in NO-sensitized rats using the experimental paradigm of nitroglycerin-induced sensitization.
The neural mechanism(s) underlying migraine remain poorly defined at present; preclinical and clinical studies show an involvement of CGRP in this disorder. However current evidence pointed out that CGRP does not exert an algogenic action per se, but it is able to mediate migraine pain only if the trigeminal-vascular system is sensitized. The present study was addressed to investigate CGRP-evoked behavior in nitric oxide (NO) sensitized rats, using an experimental model of nitroglycerin induced sensitization of trigeminal system, looking at neuropeptide release from different cerebral areas after the intra-peritoneal (i.p.) administration of NO-donors. CGRP injected into the rat whisker pad did not induce significant changes in face rubbing behavior compared to controls. On the contrary, CGRP injected in animals pre-treated with 10 mg/kg nitroglycerin significantly increased the time spent in face rubbing. Nitroglycerin pre-treated animals did not show any rubbing behavior after locally injected saline. Furthermore, the i.p. treatment with nitroglycerin produced an increase of CGRP levels in brainstem and trigeminal ganglia, but not in the hypothalamus and hippocampus. The absolute amounts of CGRP produced in the brainstem were lower compared to those in the trigeminal ganglion; however, after nitroglycerin stimulation the percentage increase was higher in the brainstem. In conclusion, findings presented in this study suggest that CGRP induces a painful behavior in rats only after sensitization of trigeminal system; thus supporting the concept that a genetic as well as acquired predisposition to trigemino- vascular activation represents the neurobiological basis of CGRP nociceptive effects in migraineurs.

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Chapter 8 - Experimental models of migraine

Abstract

Introduction

Section snippets

In vitro

Neurovascular Models

Genetic Factors and Migraine

Acknowledgment

Neuropharmacology

Neurobiol Dis

Pain

Neuropharmacology

Brain Res

Brain Res

Eur J Pharmacol

Lancet

Brain Res

Eur J Pharmacol

Pain

Neuroscience

Neurotoxicology

Pain

Eur J Pharmacol

Early Hum Dev

Brain Res

Eur J Pharmacol

Brain Res Rev

Pain

Neurosci Lett

Brain Res Mol Brain Res

Neuroscience

Trends Pharmacol Sci

Cell

Neurosci Lett

Neurosci Lett

J Biol Chem

Brain Res

Neuropharmacology

Prog Neurobiol

Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels

Br J Pharmacol

Vanilloid type 1 receptors (VR1) on trigeminal sensory nerve fibres play a minor role in neurogenic dural vasodilatation, and are involved in capsaicin-induced dural dilation

Br J Pharmacol

Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors

Br J Pharmacol

Nerve fibers and their terminals of the dura mater encephali of the rat

Anat Embryol (Berl)

The effects of pyrilamine and cimetidine on mrna c-fos expression and nociceptive flinching behavior in rats

Anesth Analg

Suppression of cortical spreading depression in migraine prophylaxis

Ann Neurol

Animal models of migraine: looking at the component parts of a complex disorder

Eur J Neurosci

Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model

Nat Med

No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery

Br J Pharmacol

Reduced threshold for cortical spreading depression in female mice

Ann Neurol

Chemical stimulation of the intracranial dura induces enhanced response to facial stimulation in brain stem trigeminal neurons

J Neurophysiol

The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater

Br J Pharmacol

Attenuation by butalbital of capsaicin-induced c-fos-like immunoreactivity in trigeminal nucleus caudalis

Headache

Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2

Nat Genet

Blockade of porcine carotid vascular response to sumatriptan by GR 127935, a selective 5-HT1D receptor antagonist

Br J Pharmacol

Pharmacology of triptans

Emerg Drugs

Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells

Neuroscience

The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel

N Engl J Med

Nitrolglycerin as a provocative agent in cluster headache

Arch Neurol

Vanilloid type 1 receptors (VR₁) on trigeminal sensory nerve fibres play a minor role in neurogenic dural vasodilatation, and are involved in capsaicin-induced dural dilation

No contractile effect for 5-HT_1D and 5-HT_1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery

Haploinsufficiency of ATP1A2 encoding the Na⁺/K⁺ pump α2 subunit associated with familial hemiplegic migraine type 2

Blockade of porcine carotid vascular response to sumatriptan by GR 127935, a selective 5-HT_1D receptor antagonist