Current Pain and Headache Reports (2018) 22:44

https://doi.org/10.1007/s11916-018-0693-5

CHRONIC DAILY HEADACHE (SJ WANG, SECTION EDITOR)

Animal Models of Chronic Migraine

Tse-Ming Chou 1,2 & Shih-Pin Chen 1,3,4,5,6

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Chronic migraine (CM) is a recalcitrant subtype of migraine which causes high degrees of disability, poor
treatment responses, and frequent recurrences in sufferers. However, the pathophysiological mechanisms underlying the devel-
opment and chronification of migraine attacks remain incompletely understood. A validated animal model could help to decipher
the pathogenic mechanism of the disease, facilitating the development of possible therapeutic strategies for CM. In this review,
we aimed to summarize current animal models of CM and discuss the validity of these models.
Recent Findings Several methods have been available to induce recurrent headache-like behaviors or biochemical changes in
rodents, including repeated dural application of inflammatory soup, chronic systemic infusion of nitroglycerin, repeated admin-
istration of acute migraine abortive treatment to simulate medication overuse headache, or genetic modification. These models
exhibit some features that are believed to be associated with migraine; however, none of the model can recapitulate all the clinical
phenotypes found in humans and each has its own weakness.
Summary The complex features of CM increase the difficulty of constructing a proper animal model. Nonetheless, currently
available models are valid to certain degrees. Future directions might consider simulating the spontaneity and chronicity of
migraine by combining known genetic substrates and allostatic loads into the same model.

Keywords Cortical spreading depression . Chronic migraine . Medication overuse headache . Sensitization . Trigeminovascular
system

Introduction edition, (ICHD-3) defined CM as headache at a frequency of

≥ 15 days per month for ≥ 3 months, of which ≥ 8 attacks are
Chronic migraine (CM) is a highly disabling subtype of mi- migraine or are responsive to migraine-specific treatment [3].
graine, with a global prevalence of around 2–4% [1, 2]. The CM usually develops from episodic migraine, with a conver-
International Classification of Headache Disorders, 3rd sion rate of about 3% a year [4, 5••]. The pathophysiology of
migraine chronification is elusive. Some possible pathophys-
This article is part of the Topical Collection on Chronic Daily Headache iological mechanisms of CM have been proposed, including
(1) dysfunction of the descending pain-modulating network
* Shih-Pin Chen [6, 7], (2) altered trigeminal and cranial autonomic system
chensp1977@gmail.com
function [8–10], (3) thalamic contribution to central sensitiza-
1 tion [11–13], and (4) medication-associated central sensitiza-
Institute of Neuroscience, National Yang-Ming University,
Taipei, Taiwan tion [14–18]. Along with the sensitization of the
2 trigeminovascular system, some nuclei in pain modulation
Interdisciplinary Neuroscience Program, Taiwan International
Graduate Program, Academia Sinica, Taipei, Taiwan circuits, especially those in the brainstem (e.g., periaqueductal
3 gray, locus coeruleus, raphe nucleus, and rostroventral medul-
Institute of Clinical Medicine, National Yang-Ming University,
Taipei, Taiwan la) and diencephalon (including the hypothalamus and thala-
4 mus), might be sensitized [6, 19–23]. Nevertheless, the exact
Division of Translational Research, Department of Medical
Research, Taipei Veterans General Hospital, Taipei, Taiwan pathophysiological mechanisms of CM remain to be clarified.
5 Animal models have been employed widely to study the
Department of Neurology, Neurological Institute, Taipei Veterans
General Hospital, Taipei, Taiwan pathogeneses of multiple medical disorders. Experimental
6 models of migraine have been developed and explored in past
Brain Research Center, National Yang-Ming University,
Taipei, Taiwan decades, leading to significant advances in the understanding
44 Page 2 of 8
of the potential mechanisms of the disorder and facilitating the
development of antimigraine treatments [24–29]. Although
none of these experimental animal models can reflect all of
the features of migraine, discoveries made with them have
been successfully translated into migraine therapeutics, such
as triptans [30–33] and drugs targeting the calcitonin gene-
related peptide (CGRP) and its receptor [34–36] (e.g.,
CGRP receptor antagonists [37–39] and monoclonal antibod-
ies against CGRP and its receptor [40–45••]). Thus, the con-
struction of animal models addressing distinct aspects of the
possible mechanisms of CM not only could advance our un-
derstanding of the disease, but might also contribute to the
development of therapeutic approaches to tackle this recalci-
trant subtype of migraine. However, many fewer models have
specifically targeted CM compared with migraine in general.
In this review, we aim to summarize the currently available
animal models of CM; analyze their validity, advantages, and
disadvantages from various perspectives; and propose direc-
tions for further research.
Key Determinants for the Construction of an
Effective Animal Model for CM
A valid animal model acting as a surrogate for human disease
should have five features: similarity of symptoms, observabil-
ity and measurability of behavioral phenotypes, inter-observer
reliability of assessment results, similarity of response to treat-
ment, and reproducibility of the system [46]. Thus, an ideal
animal model of CM should reasonably mimic clinical fea-
tures in patients, exhibit the chronicity of the disorder, respond
to the pharmacological interventions that are known to be
effective for CM, and involve mechanisms similar to those
identified in patients.
Because of the complexity of migraine and the intrinsic
differences between animals and humans, fulfillment of all
of these criteria is difficult. The chronification and transfor-
mation of migraine are particularly enigmatic, despite the
characterization of risk factors. Furthermore, whether animals
can actually experience “migraine” is another concern. These
obstacles exemplify some of the challenges in constructing an
animal model for CM, which must be overcome to facilitate
the development of novel diagnostic and therapeutic ap-
proaches for CM. The following are the key determinants that
we consider to be critical for the establishment of an effective
animal model of CM.
Recapitulation of the Clinical Features of Migraine
Migraine is a complex neurological disorder characterized by
typical throbbing and unilateral headache, accompanied by
nausea, vomiting, photophobia, and phonophobia [3].
Patients with migraine are more likely to have psychiatric
Curr Pain Headache Rep (2018) 22:44
comorbidities, such as anxiety and depression, which are
much worse in patients with CM [47–50]. Comorbidity with
depression and anxiety may increase headache frequency in
migraineurs [50–53]. In addition, a substantial proportion of
patients with CM is comorbid with medication overuse head-
ache (MOH) [54–56]. Thus, the phenotypes of a valid CM
model should mimic at least some of these clinical features
and comorbidities. In recent preclinical studies, various ap-
proaches have achieved the portrayal of clinical traits similar
to those of migraine, including cutaneous allodynia and me-
chanical hyperalgesia [57–62], photophobia [63], MOH
[14–16, 18], and depression and anxiety [64]. However, the
demonstration of all of these sub-phenotypes with a single
experimental paradigm is difficult. In addition, concern exists
about whether animals can experience “spontaneous”
migraine-like episodes as patients do, although behavioral
studies in mice carrying the human familial hemiplegic mi-
graine type 1 (FHM1) mutation have produced evidence sug-
gestive of spontaneous head pain upon subjection to novelty
or restraint stress [65]. In one study, a subset of a colony of
Sprague-Dawley rats also showed spontaneous episodic tri-
geminal allodynia [59]. Although far from ideal, the currently
available animal models of CM have at least in part mimicked
migraine phenomenology. Nevertheless, much remains to be
done to refine these models or create new models using novel
neuroscience or bioengineering techniques.
Representation of the Chronicity of the Disorder
Pain chronicity is associated with peripheral reorganization of
afferent signaling and changes in the sensitivity of nociceptors
and, perhaps, tactile afferents [66]. Chronification of the dis-
ease is accompanied by sensitization of the central nervous
system, causing further cortical reorganization in the brain
[66, 67]. A similar pathogenesis has been proposed for CM
[68–70]. The activation and sensitization of the
trigeminovascular system are considered to play central roles
in the pathogenesis of individual migraine attacks. Activation
of the trigeminal nociceptive nerve endings innervating the
cranial vasculature could lead to the release of vasoactive neu-
ropeptides, such as substance P and CGRP, which results in
neurogenic inflammation at the cortico-meningeal level and
subsequent sensitization of the trigeminal nociceptors [71].
Sensitized trigeminal nociceptive nerve endings increase input
to the trigeminal nucleus caudalis (TNC) via the trigeminal
ganglion (TG), causing activation of the brain regions in-
volved in pain processing. The superior salivatory nucleus is
also activated when the TNC is sensitized, leading to the di-
latation of meningeal arteries via parasympathetic innervation,
which further augments perivascular trigeminal nociceptive
inputs [72–76]. In CM, the activation and sensitization of
the trigeminovascular system and related pain circuits recur
frequently and become persistent with disease chronification,
Curr Pain Headache Rep (2018) 22:44
leading to the structural and functional reorganization of pain-
related circuits. Evidence for the brain signatures of
chronification remains scarce in currently available models.
In addition, the criteria for CM, especially headache frequency
(i.e., ≥ 15 headache days per month, of which ≥ 8 are migraine
attacks) and duration (≥ 3 months), are defined arbitrarily. It
remains to be explored which attack frequency and duration
are sufficient for CM modeling, and how long “headache sur-
rogates” should last when exogenously administered stimuli
(e.g., inflammatory soup, nitroglycerin, or pain medicine) are
discontinued. To reproduce the chronicity of the disorder in
future models, all of these factors should be taken into
consideration.
Reproduction of the Effects of Pharmacological
Interventions
As migraine progresses toward a chronic state, it becomes
more refractory to acute and chronic pharmacological treat-
ments. This relative refractoriness to treatment is a great
challenge in the modeling of CM. In addition, the lack of
knowledge about the pathophysiological mechanism and the
generalized nature of functional and structural brain abnor-
malities pose challenges in the search for potential treatments.
Currently, the only indicated acute migraine-specific therapies
are triptans and ergots, and the efficacy of both is limited for
CM. In fact, the effect of sumatriptan was found to differ
across models. In one mouse model in which chronic inter-
mittent nitroglycerin administration was used as a migraine
trigger, sumatriptan failed to abolish mechanical hyperalgesia
[58]. In a rat model involving similar intermittent nitroglycer-
in administration, sumatriptan attenuated hypoactivity and re-
duced facial expressions of pain [63]. Overuse of these acute
treatments could contribute to the chronification of migraine,
which might be taken as an advantage in the construction of a
CM model [14, 15, 61, 77], but could also complicate the
system by introducing an effect that not all patients will expe-
rience. Thus, a reliable model of CM should be predictively
validated with pharmacodynamic treatments that have been
proven to be effective in patients [26, 27], such as topiramate
[78] and the newly developed CGRP-targeting therapies
[45••], serving as positive controls [79–81].
Current Animal Models of CM
Currently, several methods are available to induce recurrent
headache-like behaviors or biochemical changes in experimental
animals, including repeated dural stimulation via epidural applica-
tion of inflammatory soup [10, 61, 62, 64, 82, 83], chronic sys-
temic infusion of the nitric oxide donor nitroglycerin [58, 63, 84•,
85, 86], and repeated administration of acute migraine abortive
treatment (e.g., sumatriptan or paracetamol) to simulate MOH
Page 3 of 8 44
[14–16, 18, 87] (Table 1). These models exhibit some features that
are believed to be associated (strongly) with migraine, including
periorbital, perimasseter, or hindpaw mechanical hyperalgesia [58,
62, 64, 82, 83]; photophobia [63, 88]; reduced locomotor activity
[10, 63, 82, 88]; nociceptive behaviors [10]; unilateral hindpaw
facial grooming [10]; facial expressions of pain [63, 88]; anxiety-
and depression-like behaviors [64]; bioelectrical alterations related
to cortical spreading depression (CSD) [16, 18, 87, 89]; activation
of inflammatory markers in the TG [14, 15, 87], increased Fos [16,
18, 90] or extracellular glutamate expression [62] in the TNC; and
alteration of CGRP-related genes in the TG and TNC [82]
(Table 1). These models are considered to be valid to certain
degrees. For example, a mouse model of chronic nitroglycerin-
induced hyperalgesia was responsive to the preventive migraine
therapies topiramate [84•] and propranolol [58], fulfilling the “pre-
dictive validity” requirement of an eligible model. However, the
same model failed to demonstrate the effectiveness of valproic
acid, another migraine preventive drug [58]. Rats receiving epidu-
ral inflammatory soup stimulation exhibited a cutaneous
allodynia-like response and hyperresponsiveness to nitroglycerin
[62] as well as increased nociceptive behaviors and unilateral
hindpaw facial grooming [10], fulfilling the “face validity” (i.e.,
analogy of symptoms) of the model, although whether this model
could also fulfill construct validity (i.e., comparable etiology) is not
without doubt.
The major critiques of these models are that they are not
naturally occurring and that the stimuli causing head pain (if
any) are supraphysiological. For example, one might argue
that the consequence of the repetitive epidural application of
inflammatory soup is likely chemical pachymeningitis, in-
stead of migraine; the behavioral changes observed after re-
peated administration of high-dose nitroglycerin might not be
due solely to its nitric oxide donor effect, but could also be
attributable to its vehicles [88]; and MOH models might not
be equivalent to CM models, as migraine rarely develops after
medication overuse in patients with no pre-existing headache
(although we cannot know for sure whether drug-naïve wild-
type rodents have pre-existing headache). In addition, respon-
siveness to triptans is not consistent across models. In a mouse
model of chronic intermittent nitroglycerin-evoked
hyperalgesia, sumatriptan was ineffective in inhibiting me-
chanical hyperalgesia, but instead aggravated the headache
surrogate hindpaw hyperalgesia [58], similar to the triptan-
induced latent sensitization MOH model in rats [14].
However, sumatriptan inhibited hypoactivity and grimace
scale scores evoked by chronic nitroglycerin infusion in rats
[63]. In addition, zolmitriptan was found to effectively inhibit
headache-like behaviors in rats treated with epidural inflam-
matory soup [10]. Chronic administration of sumatriptan [16,
89] or paracetamol [18, 87] increased susceptibility to CSD in
rats, suggesting the development of cortical hyperexcitability
in these MOH models. However, chronic daily CSD (without
repeated use of acute medication) did not increase, but
44 Page 4 of 8 Curr Pain Headache Rep (2018) 22:44

Table 1 Currently available models of chronic migraine

Models Animals Route and Endpoints Response to migraine treatment Validity Shortcomings Reference
duration of no.
administration

Repeated Rat Epiural Mechanical Zolmitriptan reduced nociceptive Face Supraphysiological [10, 61, 62,
inflamma- cannulation; hyperalgesia behaviors validi- inflammation 64, 82,
tory soup 4, 7, ≧ 21, Reduced Ketorolac reduced the nociceptive ty: +++ Allodynia is not equivalent 83]
30 days locomotor behavior and ipsilateral hindpaw Predictive to spontaneous head pain
activities facial grooming validi-
Nociceptive Amitriptyline reversed the allodynia ty: ++
behavior and decreased depression- and Construct
Unilateral anxiety-like behaviors validi-
hindpaw facial ty: ?
grooming
Anxiety- and
depression-like
behaviors
Increased
extracellular
glutamate
expression in
the TNC
Altered
CGRP-related
genes in the TG
and TNC
Nitroglycerin Rat, Intraperitoneal; Mechanical Propranolol, topiramate, and amiloride Face Effect of vehicle [58, 63,
mouse 11, hyperalgesia inhibited mechanical hyperalgesia; validi- Possibility of hypotension 84••, 85,
> 14 days Photophobia valproic acid and memantine were ty: ++ Inconsistent response to 86]
Reduced ineffective Predictive migraine treatment
locomotor Sumatriptan inhibited hypoactivity and validi- across models
activities grimace scale scores in rats but ty: +/− Allodynia is not equivalent
Facial expressions resulted in hyperalgesia in mice Construct to spontaneous head pain
of pain validi-
ty: +
MOH Rat Intraperitoneal; Mechanical Topiramate blocked the enhanced Fos Face No de novo headache prior [14–16, 18,
(sumatrip- 7–30 days hyperalgesia expression in the TNC and inhibited validi- to MOH 87]
tan and CSD-related cutaneous allodynia ty: ++ Allodynia is not equivalent
paraceta- bioelectrical Predictive to spontaneous head pain
mol) alterations validi-
Activation of ty: +
inflammatory Construct
markers in the validi-
TG ty: ?
Increased Fos
expression in
the TNC
Spontaneous Rat – Spontaneous Valproic acid prevented the Face Allodynia is not equivalent [59]
trigeminal episodic spontaneous changes in trigeminal validi- to spontaneous head pain
allodynia trigeminal allodynia ty: ++ Chronicity needs to be
allodynia Predictive defined
validi-
ty: +
Construct
validi-
ty: +
Monogenic FHM1 – Photophobia Rizatriptan reduced head grooming Face Monogenic form of [65]
migraine R192Q Unilateral head validi- migraine is not
mutation trans- grooming ty: ++ completely the same as
genic Lateralized Predictive common polygenic
mice winking/- validi- migraine
blinking ty: + Chronicity needs to be
Construct defined
validi-
ty: +++

Construct validity denotes comparable etiology. Face validity denotes analogy of symptoms. Predictive validity denotes responsiveness to migraine
treatment. Strong: +++, moderate: ++, mild: +, inconsistent: +/−, uncertain: ?
CGRP calcitonin gene-related peptide, MOH medication overuse headache, TG trigeminal ganglion, TNC trigeminal nucleus caudalis
Curr Pain Headache Rep (2018) 22:44
suppressed, CSD susceptibility in mice [91]. Differences
among models, including those in animal species, kindling
method, and pain surrogate, might contribute to the discrep-
ancy of findings; however, the heterogeneity also suggests an
imminent need for an ideal model of CM. Spontaneous tri-
geminal allodynia in rats [59] and transgenic mouse models of
monogenic migraine [92] with spontaneous headache-like be-
haviors (such as those of mice carrying the human FHM1
R192Q missense mutation in the Cacna1a gene [65]) is prob-
ably more phenomenologically and pathophysiologically sim-
ilar to migraine. However, operational definitions of the fre-
quency and duration of spontaneous headache-like events
might be required to characterize the extent to which these
models can represent the recalcitrant subtype of migraine.
Unsolved Problems and Future Directions
for Animal Models of CM
Drivers of Migraine Chronification
Sensitization of the central trigeminothalamic pathways may be
an important cause of CM [5••, 93]. Such sensitization might
occur during repeated migraine attacks through impaired de-
scending inhibition and/or enhanced descending facilitation of
nociception [94, 95]. In addition, affective pain regions, such as
the insula and amygdala [11] or hypothalamus [96], might also
be important mediators in the chronification of migraine.
Elucidation of the roles of these structures during and following
repetitive sensitization at the molecular, cellular, and circuit
levels might enable the construction of more ideal CM models
and generation of novel disease-modifying therapies. Given the
complex pathogenesis of CM, this disorder can be modeled
practically with a single phenotype or endophenotype serving
as a surrogate (as in most current models), as opposed to model-
ing of the entire phenotypic spectrum. Recently, two animal
models of MOH suggested a possible role of the amygdala in
the chronification of headache [90, 97]; these models are good
examples for further advancement of our knowledge.
Nevertheless, given the shortcomings mentioned above, direct-
ly inferring MOH models as CM models might not be correct.
Before the genesis of an ideal CM model, it is mandatory to
validate the findings using different model systems.
Spontaneous Nature of Migraine Attacks
The most currently available animal models are constructed using
different kinds of repeated stimuli. To make the model convincing
and pathophysiologically closer to human migraine, spontaneous
attacks or more physiological triggers are needed. The use of
genetic animal models might be a good approach. To simulate
common migraine, rather than rare monogenic forms of migraine
[92], researchers might consider using modern gene-editing
Page 5 of 8 44
techniques to introduce multiple genetic variants identified through
genome-wide association studies [98, 99]. Of course, the genesis
and chronification of migraine are not purely genetic; multiple
factors should be considered simultaneously. Whether increased
allostatic loads via the introduction of one or more migraine risk
factors [100] increase the frequency of spontaneous attacks would
be of interest. An alternative approach might be to interrogate
specific nuclei or cellular groups via more physiological ap-
proaches, such as optogenetics or chemogenetics, to see whether
the perturbation of neural circuits via these techniques could reca-
pitulate migraine phenomenology and whether repeated stimuli
could replicate specific features of CM.
Conclusions
This review raises critical points for the construction of an
animal model of CM. We propose essential components for
a validated animal model of CM, describe the major contribu-
tions and shortcomings of currently available models, and
highlight future directions for CM modeling in animal studies.
The construction of a reliable animal model of CM is one step
toward the ultimate goal of developing preventive therapies to
halt progression from the episodic to the chronic state in
humans, as these models provide a platform for testing of
the efficacy of potentially useful medications.
Funding Acknowledgment This work was supported by Taipei
Veterans General Hospital (V106C-117 to S.P.C) and the Ministry
of Science and Technology of Taiwan (MOST 104-2314-B-075 -
006 -MY3, 106-2321-B-010-009, and 107-2321-B-010-001 to
S.P.C). The funders had no role in the study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Compliance with Ethical Standards
Conflict of Interest Tse-Ming Chou and Shih-Pin Chen declare no con-
flict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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