An underrepresented majority: A systematic review utilizing allodynic criteria to examine the present scarcity of discrete animal models for episodic migraine

Abstract

Background

Despite increasing evidence differentiating episodic and chronic migraine, little work has determined how currently utilized animal models of migraine best represent each distinct disease state.

Aim

In this review, we seek to characterize accepted preclinical models of migraine-like headache by their ability to recapitulate the clinical allodynic features of either episodic or chronic migraine.

Methods

From a search of the Pu bMed database for “animal models of migraine”, “headache models” and “preclinical migraine”, we identified approximately 80 recent (within the past 20 years) publications that utilized one of 10 different models for migraine research. Models reviewed fit into one of the following categories: Dural KCl application, direct electrical stimulation, nitroglycerin administration, inflammatory soup injection, CGRP injection, medication overuse, monogenic animals, post-traumatic headache, specific channel activation, and hormone manipulation. Recapitulation of clinical features including cephalic and extracephalic hypersensitivity were evaluated for each and compared.

Discussion

Episodic migraineurs comprise over half of the migraine population, yet the vast majority of current animal models of migraine appear to best represent chronic migraine states. While some of these models can be modified to reflect episodic migraine, there remains a need for non-invasive, validated models of episodic migraine to enhance the clinical translation of migraine research.

Keywords

Chronic migraine migraine animal models translational research

Introduction

As research into novel treatments for migraine grows, so too does the need for validated animal models of migraine. Migraine carries an annual cost of around $17 billion in the US, with a female to male prevalence ratio of roughly 3:1 (1–4). Migraine is identified as an attack of unilateral, throbbing headache-like pain that lasts for up to 72 hours and may be associated with photo/phonophobia, nausea, and/or aura (5). There are significant comorbidities of migraine with stroke and epilepsy (5,6), as well as psychiatric conditions such as anxiety, depression, bipolar disorder, and panic disorder (7 –9). Unfortunately, treatment is generally empiric and focuses on symptom relief; loss of therapeutic efficacy over time can further complicate migraine management (9 –11).

Migraine may be classified as migraine with aura and migraine without aura. Aura presents as altered cortical function that typically coincides with the presence of migraine pain, and it may be related to visual, tactile, speech/language, or motor function (5). Pathophysiologically, aura is correlated with a phenomenon known as cortical spreading depression (CSD). CSD can be detected using an electroencephalogram (EEG) as a slow propagating (2–6 mm/min) wave of depolarization of neurons and glia (12). Whether CSD is a trigger of migraine and if CSD occurs in the absence of aura has been debated (5,12), but it does provide evidence of a pathophysiologic distinction between subtypes of migraine.

Similarly, migraine may be classified as either episodic migraine (EM) or chronic migraine (CM). The Silberstein-Lipton criteria define CM as > 15 days with headache in a month alongside associated migraine episodes (13). It is rare for a patient to present with primary CM, and the rate of the transformation from EM to CM is roughly 2.5% of patients per year (14,15). EM and CM can also be distinguished physiologically. In general, migraine can be explained as a state of CNS hyperexcitability, and it has been proposed that CM is a manifestation of “never ending” EM hyperexcitability (16,17). Evidence of neuronal remodeling in chronic pain disorders supports this proposition. Patients who experience chronic pain have been shown to have increased density of synapses in nociceptive pathways, loss of spinal inhibitory pathways, and increased cortical representation of pain triggering regions (17). In addition, as compared to EM patients, CM patients have higher basal blood levels of calcitonin gene-related peptide (CGRP), a vasoactive peptide with known associations in migraine (5,12,19).

In terms of treatment, CM and EM patients show marked differences in responsiveness to traditional therapy options (15,20,21). Specifically, botulinum neurotoxin-A carries FDA approval for CM, but not EM (15). There are also differences in the clinical presentation of CM and EM patients. Cutaneous allodynia (CA) is often used as an indicator of the increased sensory sensitization experienced by migraine patients, and there is a growing body of evidence that suggests differences in the CA experienced by CM and EM patients. In evaluating CA in approximately 11,000 migraineurs, Lipton et al. reported that the prevalence of CA increased as migraine frequency increased (22). Comparing cephalic to extracephalic CA, studies suggest CM patients are more likely to experience extracephalic CA than EM patients (23 –25), and the presence of both cephalic and extracephalic CA represents a risk factor for transformation from EM to CM (26). Building on this, Guy et al. examined the mechanistic differences in allodynia between cephalic and extracephalic sites for migraine patients, reporting that cephalic allodynia was primarily mechanical in nature, while extracephalic allodynia was primarily thermal (25). Given these data, CM and EM are clearly two distinct disease states with their own physiologic and clinical correlates.

Despite this evidence, little work has been performed to determine whether current animal models of migraine are truly representations of EM versus CM; this review seeks to fill this void. Whereas prior reviews on this subject have focused solely on the ability of models to recapitulate CM (27,28), we will place a focus on animal model similarity and validity to an EM or CM patient utilizing allodynic criteria. We will review the benefits and limitations of a wide range of available models, including models inducing CSD: Dural KCl application and electrical stimulation; vasoactive models: Nitroglycerin administration, inflammatory soup injection, and CGRP injection; and models priming animals to stress: Medication overuse, monogenic animals, post-traumatic headache, specific channel activation, and hormone manipulation.

Models inducing CSD

CSD was first documented in the 1940s in a series of papers by Leão and Lashley (29 –33). Since that time, numerous studies have attempted to elucidate its function in migraine and headache, but its exact role remains unclear. For an excellent history of the scientific understanding of CSD, see the 2010 review published by Tfelt-Hansen (34). Initial animal studies of CSD focused primarily on changes in regional cerebral blood flow, noting hyperemia during the wave of CSD, followed by persistent oligemia (35 –37). These studies utilized direct electrical stimulation and cortical KCl administration to induce CSD in rats. As the profile of pain research has grown in recent decades, models of migraine-like pain in rats utilizing these protocols have emerged.

CSD induced via cortical administration of KCl or electrical stimulation has been shown to activate meningeal nociceptors, providing evidence of the connection between induced CSD and migraine-like pain associated with aura (38,39). However, in 2010 Zhang et al. reported that KCl administration was more effective at reliably inducing CSD events than electrical stimulation (38). Fioravanti et al. utilized the KCl protocol to study the pain behavior profile of CSD-induced rats in 2011, reporting significantly lowered pain thresholds in both periorbital and hind-paw sites via von Frey filament testing that required activation of trigeminal afferents independent of CSD induction (40). This conclusion of similar CA induction is supported by evidence that CSD induced via KCl administration leads to uniform activation of cortical cutaneous nociceptive field territories (41). Other studies utilizing similar cortical KCl protocols in animals have attempted to further characterize the effects of CSD on blood-brain barrier (BBB) permeability and brain activity, as well as characterizing the effects of prophylaxis on CSD propagation (42 –49) (see Figure 1 for timelines of CSD-inducing models). These studies show that prophylactic administration of common migraine treatments can reduce the number of induced CSD events; however, these effects are not uniform (50,51). Key sex differences in CSD induction have also been recapitulated in ovariectomized rats, mirroring important epidemiological distinctions between the male and female population (4,52). Recent advancements in optogenetic technologies have also allowed for remote induction of CSD via transgenic light-sensitive channels (53). Arenkiel et al. did not, however, examine pain behaviors following optogenetic CSD induction (53); other pain studies utilizing this method have utilized light-sensitive channels expressed outside of the trigeminal nociceptive pathway, limiting the migraine conclusions that can be made with our allodynic criteria (54,55).

Figure 1.

Timelines of CSD inducing models. For Cottier et al., testing with topiramate was carried out 30 min prior to KCl-induced CSD. For Bolay et al., prophylactic treatment was carried out with sumatriptan (given 15 min prior to CSD), MK-801 (an N-methyl-D-aspartate receptor antagonist given 15 min prior to CSD), or L-733,060 (a neurokynin-1 receptor antagonist given 1 h prior to CSD).

Several factors should be considered when using these CSD models. First, CSD events do not occur in all migraine attacks (5). Second, significant experimental time is required to obtain valid results with these protocols (see Figure 1). Third, the literature supports that cortical pinprick alone can initiate CSD (38 –40,44). Experiments not allowing for recovery following cannula or electrode implantation are at risk of detecting confounding CSD waves. Finally, and of primary interest to this review, is the ability of these models to recapitulate the allodynic features of CM or EM patients. The conclusion that CSD induction triggers both cephalic (periorbital) and extracephalic (e.g. hind-paw) allodynia is supported by behavioral and EEG data (40,41,44). Given that CSD is a requisite factor of this model, and that both extracephalic and cephalic allodynia are induced, the CSD-induced animals are most directly clinical correlates to CM patients with aura (5,23 –26). However, this conclusion is limited by a lack of behavioral data comparing mechanical to thermal allodynia in CSD-induced animals to align with clinical reports (23 –26).

Vasoactive models

While the “vascular hypothesis” of migraine has been modified over time, evidence remains of the importance of neurovasculature and other vasoactive molecules to the etiology of migraine (11,56,57). As such, multiple groups induce migraine-like pain in animals via injections of vasoactive substances like nitroglycerin (NTG), CGRP, or a mixture of prostaglandins and other proinflammatory substances, deemed an inflammatory soup (IS) (58 –76). (see Figure 2 for timelines of vasoactive models). These models are drawn from clinical observations that migraineurs are highly sensitive to these stimuli, and that vasoconstrictive medications (i.e. triptans) can function as effective abortive agents (10,77,78).

Figure 2.

Timelines of vasoactive models. In the acute treatment model, Pradhan et al. administered ip sumatriptan 75 min after ip NTG administration and 45 min prior to behavior testing. Intrathecal injections were performed as negative controls.

NTG functions as a pro-drug for NO, driving changes to meningeal and cortical blood flow as well as numerous other downstream effects on injection (79 –82). The use of NTG as a model for migraine is supported by evidence that it can trigger migraine in human patients (78). Studies administering NTG to animals have described mixed results with acute administration, but uniformly report increased nociceptive behavior following chronic treatment (58 –62). Following 2 weeks of chronic intra-peritoneal (ip) NTG injections, both rats and mice show increased mechanical allodynia in cephalic and extracephalic sites (58,60,62). Adding to this, in 2018 Kim et al. reported that NTG-induced allodynia in mice is primarily thermal in cephalic sites and mechanical in extracephalic sites (63). The work from Sufka et al. supports this conclusion, as no tail thermal allodynia was reported in their studies on NTG-induced allodynia in rats (58). However, Greco et al. did report tail thermal allodynia following chronic ip NTG, and Bates et al. reported both thermal and mechanical allodynia in hind-paw sites following NTG administration (64,65). Thus, it remains unclear whether the NO donors can induce distinct hypersensitivities respective to anatomical fields.

It should be noted that rather than functioning as an NO donor, it has been suggested that NTG induces migraine-like pain through degranulation of mast cells or through the NO-guanylate cyclase pathway (79 –81). In support of this, there is evidence that degranulation of mast cells can trigger dural nociceptive pathways (83). Recent rodent studies have shown that activation of toll-like receptors and protease-activated receptors can lead to photophobic behaviors and hypersensitivity of cephalic and extracephalic sites (84,85). Other NO donors have also been utilized, such as sodium nitroprusside, which may offer improvements to the vehicle instability of NTG protocols (86).

Studies utilizing the IS approach typically utilize dural cannula and have reported facial and hind-paw allodynia in their behavioral results (67,68). Importantly, Melo-Carrillo et al. documented ipsilateral allodynia induced by IS administration, recapitulating the unilateral nature of migraine pain (5,69). Chronic treatment with IS has also been shown to induce depressive and anxious behaviors in rats, mirroring migraine’s comorbidities with psychiatric conditions (7 –9,67). Other studies utilizing IS protocols have demonstrated key sex differences in susceptibility between male and female rats, as well as evidence of changes in BBB permeability (70,71). However, there is limited clinical evidence for the role of prostaglandins and other IS substances in migraine patients. Thus, it has been suggested that the pain induced by these protocols is closer to that of pachymeningitis-associated headache (27,87).

Protocols utilizing CGRP have employed dural cannulation, ip injection, and IV injection as means of administration (72 –76). The latter was used in a recent test of human subjects, which reported that CGRP infusion induced headache in roughly 90% of healthy participants (77). These results, as well as evidence of the role of CGRP in migraine and the success of current trials of anti-CGRP antibodies and CGRP receptor antagonists, provide support for the CGRP model (88,89). However, sumatriptan was an ineffective treatment for CGRP-infused patients despite evidence that it inhibits CGRP expression from rat trigeminal ganglia (77,90). In 2009, Marquez de Prado et al. increased genetic expression of a component of the CGRP receptor, which resulted in mechanical hypersensitivity to mice hind-paw sites (73). Following acute exposure to CGRP in rodents, Yao et al. reported decreased grooming and exploration (74), Mason et al. reported increased photophobic behavior (75), and Rea et al. reported increased grimacing behavior (76). Given the presence of hind-paw hypersensitivity and facial grimacing, it is most likely that the preclinical CGRP models are representing the allodynic features of CM (23 –26).

Comparing and classifying the vasoactive models is challenging. The NTG protocol calls for ip injections, which cuts down on surgery and recovery time; however, only chronic administration reliably induced allodynia (58 –62). The IS protocols can acutely trigger allodynia, but they require significant time for cannulation surgery and recovery (67 –70). These models show mixed responses to prophylactic and abortive treatment as well (59,60,62,64,69,72,77). Both models appear to induce whole body allodynia, therefore they are most closely mirroring the presentation of a CM patient or one transitioning from EM to CM (23 –26). However, further testing with parallel endpoints is required to determine if these effects are uniform across the vasoactive models and are extrapolated to the clinical setting.

Models priming animals to stress

Medication overuse

In patient studies of medication overuse, it has been found that chronic use of opioids and/or triptans is associated with development of CM. In addition, elimination of these medications can reverse CM to EM (91). It has been suggested that chronic use of analgesics may lead to loss of diffuse noxious inhibitory controls, leading to chronic pain states (92). For these reasons, animal models of migraine-like pain have been developed that rely on chronic dosing of opioids (93 –95), triptans (96 –99), and NSAIDs (99 –101).

Generally, these protocols call for 1–4+ weeks of continuous ip or subcutaneous dosing followed by endpoint measurement (see Figure 3 for timelines of models priming animals to stress). This can lead to these experiments having significant cost in terms of time expenditure and drug expenses. Mechanistically, these studies show that chronic dosing of triptans, morphine, and acetaminophen increases excitability in cortical sensory regions and the trigeminal nucleus caudalis (93 –99,101). There is also evidence that medication overuse in animals leads to increased susceptibility to both KCl- and NTG-induced CSD (96,97,100,101). For morphine and NSAID dosing protocols, there is evidence that overuse increases whole-body CA, reflecting the allodynic features of CM (23 –26,93,99). De Felice et al. and Green et al. have also reported that chronic sumatriptan dosing leads to increased CA in cephalic and extracephalic sites (96,97). In 2018, however, Buonvicino et al. published differing behavioral data drawn from a similar protocol that used eletriptan instead. Their data show that chronic eletriptan dosing leads to cephalic mechanical hypersensitivity and extracephalic thermal hypersensitivity, without evidence of extracephalic mechanical hypersensitivity (99). Patient studies support the conclusion that medication overuse models have similar correlates to CM (91); however, it is possible that chronic sumatriptan and eletriptan administration represent two distinct models. Whereas chronic sumatriptan induces whole-body CA, reflecting the clinical presentation of CM, chronic eletriptan comes close to recapitulating the features of EM (i.e. primary cephalic CA) (23 –26,96,97,99). This conclusion requires further validation; however, the documented differences between chronic sumatriptan and eletriptan dosing should be considered by researchers intending to utilize these models.

Figure 3.

Timelines of other models. Following one week of recovery from mCHI, Bree et al. administered one dose of ip sumatriptan 2 h prior to pain threshold measurement. In a separate experiment, Bree et al. administered monoclonal antibodies to CGRP every 6 days while animals recovered. Similarly, Sandweiss et al. allowed rats to recover for 1 week following ovariectomy, then administered ip sumatriptan 2 h prior to E2 testing.

Monogenic animals

While an exact genetic component of migraine has yet to be elucidated, the possibility of generating knock-in animal models of migraine presents an exciting avenue for pain research. One avenue focuses on knock-in models of familial hemiplegic migraine (FHM) (102 –106). FHM is a rare diagnosis of congenital migraine with motor aura (hemiplegia), for which three mutated loci affecting ion channel conductance, termed FHM 1, 2, and 3, have been identified (107). These mutations are also associated with development of epilepsy, mirroring its comorbidity with migraine (5,6,108). Studies utilizing FHM knock-in animals have recapitulated numerous clinical features of migraine, including unilateral pain induction, responsiveness to triptans, induction of anxious and depressive behaviors, photophobia, and sex differences in susceptibility to CSD (103,105,106). However, Chanda et al. reported evidence of unilateral pain via observation of grooming behaviors; in their study, they report no pain threshold differences between wild-type and knock-in mice for exogenous stimuli (105). Notably, there is evidence that these animals are susceptible to spontaneous attacks of hemiplegia, recapitulating a feature of FHM, but not CM or EM (103). As recognized by Chen et al. in their review of monogenic models of migraine, clinical differences between FHM and migraine challenge translatability (109). These protocols are also limited by the extensive time requirement to produce monogenic knock-in animals (see Figure 3).

Other genetic models utilized to study migraine pathophysiology induce spontaneous trigeminal allodynia (STA) (110), familial advanced sleep phase syndrome (FASPS) (111), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (112). Interestingly, initial studies of STA rats have reported divergent results. In 2012, Oshinsky et al. reported their STA rats to best correlate with episodic headache (110), but in 2018 Munro et al. stated that STA rats better recapitulate the features of CM (113). Despite this difference, both studies reported STA rats displayed solely cephalic CA and were responsive to traditional migraine therapies (110,113). It should also be noted that recent genome-wide association studies have identified novel loci mutations in families with high rates of CM and EM (114,115). With further research, it is possible that new genetic models of migraine may be developed, and that these models will distinctly correlate with CM or EM.

Post-traumatic headache

In neurological practice, there is a well-documented link between traumatic brain injury (TBI) and headache. This subclass of headache is termed post-traumatic headache; however, it shares many features with EM and CM (116). In attempts to limit invasive procedures, numerous protocols incite migraine-like pain in animals via a single induced mild closed-head injury (mCHI) (117 –120) or via controlled cortical impact (121,122). Following injury, animals recover for a period of 2–12 weeks prior to data collection (117 –121).

Tissue analyses of animals exposed to both injuries show increases in serum CGRP levels following recovery, as well as increased expression of CGRP in the trigeminal nucleus, providing evidence of a pathophysiological effect of TBI that aligns with migraine (117,120). Studies of CSD induction have also demonstrated that animals show increased sensitivity to KCl and NTG following mCHI (119,120). Documenting pain behavior profiles, Bree et al. have reported in two papers that mCHI induces cephalic mechanical hypersensitivity in male and female rats, without evidence of extracephalic CA (117,118). These results may be interpreted as confounding effects of the head injury; however, Bree et al. reported that both sumatriptan and monoclonal antibodies to CGRP were able to ameliorate the induced allodynia (117,118). In addition, Moye et al. reported no significant difference between extracephalic and cephalic CA in mice exposed to NTG following mCHI (120). If soft tissue damage from the head injury was increasing cephalic allodynia, a difference would be expected between anatomical sites following NTG administration. As it appears to primarily induce cephalic CA, the mCHI model may be closely correlated with EM, yet it is not reflective on many migraineurs (i.e. no known physical trauma) (23 –26). Models utilizing controlled cortical impact are subject to similar limitations; however, behavioral data from these studies show induced cephalic and extracephalic CA, mirroring the allodynic features of CM rather than EM (23 –26,122).

Further experimentation comparing mechanical to thermal allodynia is necessary for complete validation of the TBI models. It should also be noted that a recent MRI study comparing post-traumatic headache patients to migraineurs concluded that the two conditions stem from different neural pathophysiologic states (123). For these reasons, the TBI models may be limited; however, they present appealing limited-invasive options to inducing migraine-like pain in animals.

Specific channel activation

In 2019, the Dussor lab published their work on a novel model of migraine, which calls for direct injection of low pH synthetic interstitial fluid (SIF) into the dura of animals (124). This was built on prior cannulation studies that demonstrated SIF with a pH of 5–6 activated meningeal acid sensing ion channels (ASICs) to incite dural nociception (125,126). They further established that amiloride, an ASIC antagonist, was able to block these effects (126). Their protocol is exciting, as it may allow for rapid induction of migraine-like pain with minimally invasive procedures; however, they acknowledge that accurate injection of SIF into the dura requires precise calculation of the depth of the sagittal suture (124). Behavioral studies utilizing this method show that low pH SIF induces both cephalic and extracephalic CA, recapitulating the allodynic features of CM (23 –26). Further testing will likely be required, however, before the pH modification protocol will be generally accepted as a valid model of CM.

Another channel type targeted for induction of migraine-like pain are transient receptor potential ankyrin 1 (TRPA1) channels. It has been shown that activation of TRPA1 channels can induce CSD (127), and two TRPA1 agonists, umbellulone and mustard oil, have been tested in rodent models to evaluate their behavioral effects (128,129). Like activation of ASICs, both umbellulone and mustard oil induce facial and hind-paw mechanical hypersensitivity (115). In this sense, TRPA1 agonists may be able to recapitulate the features of CM (23 –26); however, patient reports of umbellulone exposure document induction of cluster headache rather than migraine (130).

Hormonal manipulation

Finally, it has been proposed that administration of high dose hormones is sufficient to trigger migraine in animals. A 2018 study of male patients with either EM or CM demonstrated that, as compared to controls, males with migraine have significantly higher levels of interictal 17-β-Estradiol (E2) (131). Furthermore, there is evidence that animals with higher blood levels of E2 are more susceptible to induced CSD (132). These data, combined with the increased prevalence of migraine in the female population, suggest a role for the hormone E2 in migraine development (4). In 2017, Sandweiss et al. published a protocol for inducing migraine-like pain in rodents, in which ovariectomized rats received a single ip bolus of high dose E2 (133). These rats demonstrated decreased exploratory behavior and decreased periorbital pain thresholds. Importantly, these effects were ameliorated by administration of either sumatriptan or an E2 antagonist, providing support for the conclusion that migraine was induced and that estrogen receptors are necessary to produce this effect (133). This study did not, however, examine extracephalic pain thresholds, limiting the conclusions that can be made about its ability to recapitulate the features of EM or CM. Furthermore, clinical correlations between the female menstrual cycle and migraine development suggest that E2 may not be the only hormonal trigger for migraine (134). The E2 administration protocol represents an interesting alternative to inducing migraine-like pain in animals, yet additional experimentation with pain threshold testing at both cephalic and extracephalic sites will be required prior to its validation.

Discussion

This review attempted to shed light on the ability of currently available animal models of migraine to recapitulate the allodynic features of either CM or EM. The criteria for classification were based upon patient data, which indicate that both cephalic and extracephalic CA show a higher incidence in CM patients (23 –26) (see Table 1 for a summary of model classifications).

Table 1.

Summary of model classifications.

Model	Number of studies Reviewed	Cephalic allodynia induced?	Extracephalic allodynia induced?	Mechanical and thermal hypersensitivity tested?	Correlates to CM or EM?	Comments
Dural KCl administration	15	Yes	Yes	No	CM	More effective at inducing CSD than DES
Direct electrical stimulation	5	–	–	–	–	Presence of electrodes limits behavioral measurements
Nitroglycerin injection	14	Yes	Yes	Yes	CM	Induced cephalic thermal allodynia and extracephalic mechanical allodynia
Inflammatory soup administration	5	Yes	Yes	No	CM	Induced psychiatric symptoms and unilateral pain
CGRP injection	5	–	Yes	No	–	Limited pain threshold data available
Medication overuse	11	Yes	Yes	Yes	CM	Eletriptan overuse induced cephalic mechanical hypersensitivity with only thermal extracephalic hypersensitivity
Monogenic animals (FHM KI)	10	No	No	Yes	–	No significant difference in thresholds to exogenous stimuli compared to WT mice for FHM KI
Post-traumatic headache	6	Yes	No	No	EM	MRI data shows PTH and migraine arise from different mechanisms
Specific channel activation	6	Yes	Yes	No	CM	pH protocol requires calculation of depth of sagittal suture
Hormone manipulation	1	Yes	–	No	–	Extracephalic allodynia not evaluated

CM: chronic migraine; EM: episodic migraine; CSD: cortical spreading depression; DES: direct electrical stimulation; CGRP: calcitonin gene-related peptide; FHM: familial hemiplegic migraine; KI: knock-in; WT: wild type; PTH: post-traumatic headache.

Two pertinent conclusions from this review warrant discussion. First, the lack of uniformity in the outcome measures reported by these studies precludes full comparison. In 2008, Rice et al. published a call for uniform reporting standards in animal models of pain states (135); over a decade later, we reaffirm this call. Based on patient data, experiments studying animal models of migraine need to report both mechanical and thermal pain thresholds at cephalic and extracephalic sites to strengthen conclusions drawn and increase translational application. In addition, the specific methods of measuring allodynia in animals lacks homogeneity. Specifically, von Frey filament testing, which provides an excellent means of reproducing and testing behavioral results between laboratories, was not utilized by all studies reviewed herein.

Second, it must be noted that most currently available models appear to induce the allodynic criteria of CM. Rough calculations comparing the total prevalence of migraine to that of CM indicate that CM comprises approximately 10–30% of the migraine population (1,2,14). Thus, episodic migraineurs epitomize most migraine sufferers, yet this is not reflected in current animal models of migraine. Perhaps for this reason numerous analgesics proposed for the treatment of migraine have failed to translate to clinical practice, such as the 2015 trials of orexin antagonists, which were shown to be effective in treating KCl-model mice yet failed to treat migraine when administered to patients (136 –138).

We acknowledge specific limitations to our utilization of allodynic criteria as a means of classifying these models. While a significant difference between extracephalic and cephalic CA has been reported for EM and CM patients, this difference may not indicate a strict cut-off for the clinical population, rather the presence of both types of CA may represent a risk factor of transformation (23 –26). Furthermore, in contrast to Bigal et al., Benatto et al. reported no difference in extracephalic and cephalic CA for chronic and episodic migraineurs (139). The use of triptans to ameliorate the effects of models classified as CM may also limit our conclusions (60,69). Sumatriptan is commonly used as an abortive treatment for episodic migraine, yet it was effective in reducing allodynia for the NTG and IS models (3,60,69). However, sumatriptan is often avoided for CM patients, not due to lack of efficacy but because continued use can worsen symptoms associated with medication overuse (5). While these limitations exist, it is our belief that the presence of extracephalic CA reflects increased synaptic density in nociceptive pathways, as demonstrated by increased staining for c-Fos positive neurons in animals subjected to the KCl, NTG, IS, and medication overuse protocols (40,80,97,140,141). This mirrors the increase in synaptic density seen in patients with chronic pain and offers an explanation for the increased susceptibility to CSD seen in models priming animals to stress (17,96,97,100,101).

Ultimately, experimenters must exercise caution when reporting the efficacy of novel treatments and indicate whether the animal model used reflected CM or EM. The current scarcity of animal models inducing the sole features of EM presents a challenge; however, there is evidence that modifications to current models may better recapitulate the features of EM, or perhaps a novel protocol may emerge as a primary model of EM.

Article highlights

Most migraine sufferers experience episodic migraine.

The majority of currently utilized animal models of migraine appear to best recapitulate the allodynic features of chronic migraine.

The lack of validated models of episodic migraine presents a challenge to the translatability of migraine pharmacological research.

Modifications to currently utilized animal models of migraine may better recapitulate episodic migraine.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS099292, TML) of the National Institutes of Health, Arizona Biomedical Research Commission (ABRC45952, TML), and with monies from the Department of Pharmacology at the University of Arizona as well as the MD-PhD Program at the University of Arizona. Authors are solely responsible for the content, which does not necessarily represent the official views of the National Institutes of Health, the State of Arizona, or the University of Arizona.

The authors declare no competing financial interests.

ORCID iD

Aidan Levine

References

Stovner

Hagen

Prevalence, burden, and cost of headache disorders. Curr Opin Neurol 2006; 19: 281–285.

Burch

Rizzoli

Loder

The prevalence and impact of migraine and severe headache in the United States: Figures and trends from government health studies.

Headache 2018; 58: 496–505.

Goldberg

LD.

The cost of migraine and its treatment. Am J Manag Care 2005; 11: S62–S67.

Smitherman

Burch

Sheikh

, et al. The prevalence, impact, and treatment of migraine and severe headaches in the United States: A review of statistics from national surveillance studies. Headache 2013; 53: 427–436.

Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38: 1–211.

Haut

Bigal

Lipton

RB.

Chronic disorders with episodic manifestations: Focus on epilepsy and migraine. Lancet Neurol 2006; 5: 148–157.

Kao

Wang

Tsai

, et al. Psychiatric comorbidities in allodynic migraineurs. Cephalalgia 2014; 34: 211–218.

Hamelsky

Lipton

RB.

Psychiatric comorbidity of migraine. Headache 2006; 46: 1327–1333.

Negro

Sciattella

Rossi

, et al. Cost of chronic and episodic migraine patients in continuous treatment for two years in a tertiary level headache Centre. J Headache Pain 2019; 20: 120.

10.

Goadsby

Lipton

Ferrari

MD.

Migraine – current understanding and treatment. N Engl J Med 2002; 346: 257–270.

11.

Goadsby

Hargreaves

Refractory migraine and chronic migraine: Pathophysiological mechanisms. Headache 2008; 48: 1399–1405.

12.

Pietrobon

Moskowitz

MA.

Pathophysiology of migraine. Annu Rev Physiol 2013; 75: 365–391.

13.

Natoli

Manack

Dean

, et al. Global prevalence of chronic migraine: A systematic review. Cephalalgia 2010; 30: 599–609.

14.

Lipton

RB.

Tracing transformation: Chronic migraine classification, progression, and epidemiology. Neurology 2009; 72: S3–S7.

15.

May

Schulte

LH.

Chronic migraine: Risk factors, mechanisms and treatment. Nat Rev Neurol 2012; 12: 455–464.

16.

Aurora

Wilkinson

The brain is hyperexcitable in migraine. Cephalalgia 2007; 27: 1442–1453.

17.

Chronic migraine: A process of dysmodulation and sensitization. Mol Pain 2018; 14: 1–10.

18.

Kuner

Flor

Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci 2016; 18: 20–30.

19.

Cernuda-Morollón

Larrosa

Ramón

, et al. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 2013; 81: 1191–1196.

20.

Burstein

Jakubowski

, et al. The science of migraine. J Vestib Res 2011; 21: 305–314.

21.

Lipton

RB, Silberstein S, Dodick D

, et al. Topiramate intervention to prevent transformation of episodic migraine: The topiramate INTREPID study. Cephalalgia 2011; 31: 18–30.

22.

Lipton

Bigal

Ashina

, et al. Cutaneous allodynia in the migraine population. Ann Neurol 2008; 63: 148–158.

23.

Kitaj

Klink

Pain thresholds in daily transformed migraine versus episodic migraine headache patients. Headache 2005; 45: 992–998.

24.

Mathew

Kailasam

Seifert

Clinical recognition of allodynia in migraine. Neurology 2004; 63: 848–852.

25.

Guy

Marques

Orliaguet

, et al. Are there differences between cephalic and extracephalic cutaneous allodynia in migraine patients? Cephalalgia 2010; 30: 881–886.

26.

Bigal

Lipton

RB.

Clinical course in migraine: Conceptualizing migraine transformation. Neurology 2008; 71: 848–855.

27.

Chou

Chen

Animal models of chronic migraine. Curr Pain Headache Rep 2018; 22: 44.

28.

Munro

Jansen-Olesen

Olesen

Animal models of pain and migraine in drug discovery. Drug Discov Today 2017; 22: 1103–1111.

29.

Leão

AA.

Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944; 7: 359–390.

30.

Leão

AA.

Further observations on the spreading depression of activity in the cerebral cortex. J Neurophysiol 1947; 10: 409–414.

31.

Leão

AA.

Pial circulation and spreading depression of activity in the cerebral cortex. J Neurophysiol 1944; 7: 391–396.

32.

Leão

Morison

RS.

Propagation of spreading cortical depression. J Neurophysiol 1948; 8: 33–45.

33.

Lashley

KS.

Patterns of cerebral integration indicated by the scotoma of migraine. Arch Neurol Psychiatry 1941; 42: 259–264.

34.

Tfelt-Hansen

PC.

History of migraine with aura and cortical spreading depression from 1941 and onwards. Cephalalgia 2010; 30: 780–792.

35.

Lauritzen

Jørgensen

Diemer

, et al. Persistent oligemia of rat cerebral cortex in the wake of spreading depression. Ann Neurol 1982; 12: 469–474.

36.

Shimazawa

Hara

An experimental model of migraine with aura: Cortical hypoperfusion following spreading depression in the awake and freely moving rat. Clin Exp Pharmacol Physiol 1996; 23: 890–892.

37.

Wolf

Lindauer

Villringer

, et al. Excessive oxygen or glucose supply does not alter the blood flow response to somatosensory stimulation or spreading depression in rats. Brain Res 1997; 761: 290–299.

38.

Zhang

Levy

Noseda

, et al. Activation of meningeal nociceptors by cortical spreading depression: Implications for migraine with aura. J Neurosci 2010; 30: 8807–8814.

39.

Bolay

Reuter

Dunn

, et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8: 136–142.

40.

Fioravanti

Kasasbeh

Edelmayer

, et al. Evaluation of cutaneous allodynia following induction of cortical spreading depression in freely moving rats. Cephalalgia 2011; 31: 1090–1100.

41.

Zhang

Levy

Kainz

, et al. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol 2011; 69: 855–865.

42.

Kurauchi

Haruta

Tanaka

, et al. Propranolol prevents cerebral blood flow changes and pain-related behaviors in migraine model mice. Biochem Biophys Res Commun 2019; 508: 445–450.

43.

Marschollek

Karimzadeh

Jafarian

, et al. Effects of garlic extract on spreading depression: In vitro and in vivo investigations. Nutr Neurosci 2017; 20: 127–134.

44.

Cottier

Galloway

Calabrese

, et al. Loss of blood-brain barrier integrity in a KCl-induced model of episodic headache enhances CNS drug delivery. eNeuro 2018; 5: 0116–0118.

45.

Seghatoleslam

Ghadiri

Ghaffarian

, et al. Cortical spreading depression modulates the caudate nucleus activity. J Neurosci 2014; 267: 83–90.

46.

Lambert

Truong

Zagami

AS.

Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system. Cephalalgia 2011; 31: 1439–1451.

47.

Ayata

Shimizu‐Sasamata

, et al. Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the alpha1A subunit of P/Q type calcium channels. J Neurosci 2000; 95: 639–645.

48.

Yalcin

Chen

, et al. Caffeine does not affect susceptibility to cortical spreading depolarization in mice. J Cereb Blood Flow Metab 2019; 39: 740–750.

49.

Liktor-Busa

Blawn

Kellohen

, et al. Functional NHE1 expression is critical to blood brain barrier integrity and sumatriptan blood to brain uptake. PLoS One 2020; 15: e0277463.

50.

Ayata

Jin

Kudo

, et al. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol 2006; 59: 652–661.

51.

Bogdanov

Multon

Chauvel

, et al. Migraine preventive drugs differentially affect cortical spreading depression in rat. Neurobiol Dis 2011; 41: 430–435.

52.

Chauvel

Schoenen

Multon

Influence of ovarian hormones on cortical spreading depression and its suppression by L-kynurenine in rat. PLoS One 2013; 8: e82279.

53.

Arenkiel

Peca

Davison

, et al. In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2. Neuron 2007; 54: 205–218.

54.

Daou

Tuttle

Longo

, et al. Remote optogenetic activation and sensitization of pain pathways in freely moving mice. J Neurosci 2013; 33: 18631–18640.

55.

Iyer

Montgomery

Towne

, et al. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat Biotechnol 2014; 32: 274–278.

56.

Jacobs

Dussor

Neurovascular contributions to migraine: Moving beyond vasodilation. J Neurosci 2016; 338: 130–144.

57.

Waeber

Moskowitz

MA.

Migraine as an inflammatory disorder. Neurology 2005; 64: S9–S15.

58.

Sufka

Staszko

Johnson

, et al. Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats. J Headache Pain 2016; 17: 40.

59.

Tipton

Tarash

McGuire

, et al. The effects of acute and preventive migraine therapies in a mouse model of chronic migraine. Cephalalgia 2016; 36: 1048–1056.

60.

Pradhan

Smith

McGuire

, et al. Characterization of a novel model of chronic migraine. J Pain 2014; 155: 269–274.

61.

Ferrari

Levine

Green

PG.

Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat. J Neurosci 2016; 317: 121–129.

62.

Moye

Tipton

Dripps

, et al. Delta opioid receptor agonists are effective for multiple types of headache disorders. Neuropharmacology 2019; 148: 77–86.

63.

Kim

Yeo

Yoon

, et al. Differential development of facial and hind paw allodynia in a nitroglycerin-induced mouse model of chronic migraine; role of capsaicin sensitive primary afferents. Biol Pharm Bull 2018; 41: 172–181.

64.

Bates

Nikai

Brennan

, et al. Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 2010; 30: 170–178.

65.

Greco

Demartini

Zanaboni

, et al. 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. J Headache Pain 2018; 19: 51.

66.

Knapp

Szita

Kocsis

, et al. Nitroglycerin enhances the propagation of cortical spreading depression: Comparative studies with sumatriptan and novel kynurenic acid analogues. Drug Des Devel Ther 2016; 11: 27–34.

67.

Zhang

Liu

Zhao

, et al. Depression and anxiety behaviour in a rat model of chronic migraine. J Headache Pain 2017; 18: 27.

68.

Wei

Edelmayer

Yan

, et al. Activation of TRPV4 on dural afferents produces headache-related behavior in a preclinical rat model. Cephalalgia 2011; 31: 1595–1600.

69.

Melo-Carrillo

López-Avila

A chronic animal model of migraine, induced by repeated meningeal nociception, characterized by a behavioral and pharmacological approach. Cephalalgia 2013; 33: 1096–1105.

70.

Scheff

Gold

MS.

Sex differences in the inflammatory mediator-induced sensitization of dural afferents. J Neurophysiol 2011; 106: 1662–1668.

71.

Fried

Maxwell

Elliott

, et al. Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia. Cephalalgia 2018; 38: 674–689.

72.

Cumberbatch

Williamson

Mason

, et al. Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT1B/1D agonist. Br J Pharmacol 1999; 126: 1478–1486.

73.

Marquez de Prado

Hammond

Russo

AF.

Genetic enhancement of calcitonin gene-related peptide-induced central sensitization to mechanical stimuli in mice. J Pain 2009; 10: 992–1000.

74.

Yao

Huang

Wang

, et al. Behavioral study of a rat model of migraine induced by CGRP. Neurosci Lett 2017; 651: 134–139.

75.

Mason

Kaiser

Kuburas

, et al. Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms. J Neurosci 2017; 37: 204–216.

76.

Rea

Wattiez

Waite

, et al. Peripherally administered calcitonin gene-related peptide induces spontaneous pain in mice: Implications for migraine. Pain 2018; 159: 2306–2317.

77.

Falkenberg

Rønde Bjerg

Yamani

, et al. Sumatriptan does not antagonize CGRP‐induced symptoms in healthy volunteers. Headache 2020; 60: 665–676.

78.

Christiansen

Thomsen

Daugaard

, et al. Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia 1999; 19: 660–667.

79.

Olesen

The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 2008; 120: 157–171.

80.

Ben Aissa

Tipton

Bertels

, et al. Soluble guanylyl cyclase is a critical regulator of migraine-associated pain. Cephalalgia 2018; 38: 1471–1484.

81.

Pedersen

Ramachandran

Amrutkar

, et al. Mechanisms of glyceryl trinitrate provoked mast cell degranulation. Cephalalgia 2015; 35: 1287–1297.

82.

Greco

Meazza

Mangione

, et al. Temporal profile of vascular changes induced by systemic nitroglycerin in the meningeal and cortical districts. Cephalalgia 2011; 31: 190–198.

83.

Levy

Burstein

Kainz

, et al. Mast cell degranulation activates a pain pathway underlying migraine headache. Pain 2007; 130: 166–176.

84.

Ramachandran

Wang

Saavedra

, et al. Role of toll-like receptor 4 signaling in mast cell-mediated migraine pain pathway. Mol Pain 2019; 15: 1–14.

85.

Hassler

Ahmad

Burgos-Vega

, et al. Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice. Cephalalgia 2019; 39: 111–122.

86.

Avona

Mason

Lackovic

, et al. Repetitive stress in mice causes migraine-like behaviors and CGRP-dependent hyperalgesic priming to a migraine trigger. Pain. ePub ahead of print 10 June 2020. DOI: 10.1097/j.pain.0000000000001953.

87.

Fain

Mekinian

Les pachyméningites [Pachymeningitis]. Rev Med Interne 2017; 38: 585–591 (in French).

88.

Eftekhari

Wang

, et al. Cortical spreading depression as a site of origin for migraine: Role of CGRP. Cephalalgia 2019; 39: 428–434.

89.

Edvinsson

Haanes

Warfvinge

, et al. CGRP as the target of new migraine therapies – successful translation from bench to clinic. Nat Rev Neurol 2018; 14: 338–350.

90.

Durham

Russo

AF.

Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci 1999; 19: 3423–3429.

91.

De Felice

Ossipov

Porreca

Update on medication-overuse headache. Curr Pain Headache Rep 2011; 15: 79–83.

92.

De Felice

Ossipov

Porreca

Persistent medication-induced neural adaptations, descending facilitation, and medication overuse headache. Curr Opin Neurol 2011; 24: 193–196.

93.

Celerier

Rivat

Jun

, et al. Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine. Anesthesiology 2000; 92: 465–472.

94.

Robbins

Schmitt

Winterson

, et al. Chronic morphine increases Fos-positive neurons after concurrent cornea and tail stimulation. Headache 2012; 52: 262–273.

95.

Kandasamy

Dawson

Hilgendorf

, et al. Medication overuse headache following repeated morphine, but not 9-tetrahydrocannabinol administration in the female rat. Behav Pharmacol 2018; 29: 469–472.

96.

De Felice

Ossipov

Wang

, et al. Triptan-induced latent sensitization: A possible basis for medication overuse headache. Ann Neurol 2010; 67: 325–337.

97.

Green

De Felice

, et al. Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache. Cephalalgia 2014; 34: 594–604.

98.

Becerra

Bishop

Barmettler

, et al. Triptans disrupt brain networks and promote stress-induced CSD-like responses in cortical and subcortical areas. J Neurophysiol 2016; 115: 208–217.

99.

Buonvicino

Urru

Muzzi

, et al. Trigeminal ganglion transcriptome analysis in 2 rat models of medication-overuse headache reveals coherent and widespread induction of pronociceptive gene expression patterns. Pain 2018; 159: 1980–1988.

100.

Supornsilpchai

le Grand

Srikiatkhachorn

Cortical hyperexcitability and mechanism of medication-overuse headache. Cephalalgia 2010; 30: 1101–1109.

101.

Potewiratnanond

le Grand

Srikiatkhachorn

, et al. Altered activity in the nucleus raphe magnus underlies cortical hyperexcitability and facilitates trigeminal nociception in a rat model of medication overuse headache. BMC Neurosci 2019; 20: 54.

102.

van den Maagdenberg

Pietrobon

Pizzorusso

TA.

A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004; 41: 701–710.

103.

van den Maagdenberg

Pizzorusso

Kaja

High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Ann Neurol 2010; 67: 85–98.

104.

Fioretti

Catacuzzeno

Sforna

Trigeminal ganglion neuron subtype-specific alterations of Ca(V)2.1 calcium current and excitability in a Cacna1a mouse model of migraine. J Physiol 2011; 589: 5879–5895.

105.

Chanda

Tuttle

Baran

, et al. Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice. Pain 2013; 154: 1254–1262.

106.

Bøttger

Glerup

Gesslein

, et al. Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model. Sci Rep 2016; 6: 22047.

107.

Russell

Ducros

Sporadic and familial hemiplegic migraine: Pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol 2011; 10: 457–470.

108.

de Vries

Frants

Ferrari

, et al. Molecular genetics of migraine. Hum Genet 2009; 126: 115–132.

109.

Chen

Tolner

Eikermann-Haerter

Animal models of monogenic migraine. Cephalalgia 2016; 36: 704–721.

110.

Oshinsky

Sanghvi

Maxwell

, et al. Spontaneous trigeminal allodynia in rats: A model of primary headache. Headache 2012; 52: 1336–1349.

111.

Brennan

Bates

Shapiro

, et al. Casein kinase idelta mutations in familial migraine and advanced sleep phase. Sci Transl Med 2013; 5: 1–11.

112.

Eikermann-Haerter

Yuzawa

, and Dileköz

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression. Ann Neurol 2011; 69: 413–418.

113.

Munro

Petersen

Jansen-Olesen

, et al. A unique inbred rat strain with sustained cephalic hypersensitivity as a model of chronic migraine-like pain. Sci Rep 2018; 8: 1836.

114.

Anttila

Winsvold

Gormley

, et al. Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet 2013; 45: 912–917.

115.

Gormley

Kurki

Hiekkala

, et al. Common variant burden contributes to the familial aggregation of migraine in 1,589 families. Neuron 2018; 98: 743–753.

116.

Riechers

Walker

, and Ruff

RL.

Post-traumatic headaches. Handb Clin Neurol 2015; 128: 567–578.

117.

Bree

Mackenzie

Stratton

, et al. Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury. Cephalalgia 2020; 40: 748–760.

118.

Bree

Levy

Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache. Cephalalgia 2018; 38: 246–258.

119.

Hosseini-Zare

Abdulla

, et al. Effects of experimental traumatic brain injury and impaired glutamate transport on cortical spreading depression. Exp Neurol 2017; 295: 155–161.

120.

Moye

Novack

Tipton

, et al. The development of a mouse model of mTBI-induced post-traumatic migraine, and identification of the delta opioid receptor as a novel therapeutic target. Cephalalgia 2019; 39: 77–90.

121.

Elliott

Oshinsky

Amenta

, et al. Nociceptive neuropeptide increases and periorbital allodynia in a model of traumatic brain injury. Headache 2012; 52: 966–984.

122.

Macolino

Daiutolo

Albertson

, et al. Mechanical allodynia induced by traumatic brain injury is independent of restraint stress. J Neurosci Methods 2014; 226: 139–146.

123.

Schwedt

Chong

Peplinski

, et al. Persistent post-traumatic headache vs. migraine: An MRI study demonstrating differences in brain structure. J Headache Pain 2017; 18: 87.

124.

Burgos-Vega

Quigley

Dos Santos

, et al. Non-invasive dural stimulation in mice: A novel preclinical model of migraine. Cephalalgia 2019; 39: 123–134.

125.

Yan

Wei

Bischoff

, et al. pH-evoked dural afferent signaling is mediated by ASIC3 and is sensitized by mast cell mediators. Headache 2013; 53: 1250–1256.

126.

Yan

Edelmayer

Wei

, et al. Dural afferents express acid-sensing ion channels: A role for decreased meningeal pH in migraine headache. Pain 2011; 152: 106–113.

127.

Jiang

Wang

, et al. The transient receptor potential ankyrin type 1 plays a critical role in cortical spreading depression. J Neurosci 2018; 382: 23–34.

128.

Nassini

Materazzi

Vriens

, et al. The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system. Brain 2012; 135: 376–390.

129.

Edelmayer

Yan

, et al. Activation of TRPA1 on dural afferents: A potential mechanism of headache pain. Pain 2012; 153: 1949–1958.

130.

Benemei

Appendino

Geppetti

Pleasant natural scent with unpleasant effects: Cluster headache-like attacks triggered by Umbellularia californica. Cephalalgia 2009; 30: 744–746.

131.

van Oosterhout

WPJ

Schoonman

van Zwet

, et al. Female sex hormones in men with migraine. Neurology 2018; 91: 374–381.

132.

Bolay

Berman

Akcali

Sex-related differences in animal models of migraine headache. Headache 2011; 51: 891–904.

133.

Sandweiss

Cottier

McIntosh

, et al. 17-β-Estradiol induces spreading depression and pain behavior in alert female rats. Oncotarget 2017; 8: 114109–114122.

134.

Calhoun

AH.

Understanding menstrual migraine. Headache 2018; 58: 626–630.

135.

Rice

Cimino-Brown

Eisenach

, et al. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: A critical appraisal and call for uniform reporting standards. Pain 2008; 139: 243–247.

136.

Berge

OG.

Predictive validity of behavioural animal models for chronic pain. Br J Pharmacol 2011; 164: 1195–1206.

137.

Hoffmann

Supronsinchai

Akerman

, et al. Evidence for orexinergic mechanisms in migraine. Neurobiol Dis 2015; 74: 137–143.

138.

Chabi

Zhang

Jackson

, et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia 2015; 35: 379–388.

139.

Benatto

Florencio

Carvalho

, et al. Cutaneous allodynia is more frequent in chronic migraine, and its presence and severity seems to be more associated with the duration of the disease. Arq Neuropsiquiatr 2017; 75: 153–159.

140.

Zhou

Wang

, et al. Inhibition of nerve growth factor signaling alleviates repeated dural stimulation-induced hyperalgesia in rats. Neuroscience 2019; 398: 252–262.

141.

Strassman

Mineta

Vos

BP.

Distribution of fos-like immunoreactivity in the medullary and upper cervical dorsal horn produced by stimulation of dural blood vessels in the rat. J Neurosci 1994; 14: 3725–3735.