Animal Models Of Migraine Headaches: Towards Improved Understanding Of Disease Etiology And Biological Mechanisms
What Do We Know About Migraines?
Migraines are best known for their severe, pulsating headaches, along with more variable associated symptoms such as hypersensitivity to lights and sounds, nausea and vomiting, or the manifestation of auras.
It is a neurological disorder that is highly prevalent, and the chronic nature of migraine is extremely debilitating, making it one of the leading causes of disability.[2, 3, 4, 5] There is a clear gender difference in prevalence (3:1 female: male), and the peri-pubertal onset and familial link suggest developmental and genetic factors in migraines.[2, 6, 7, 4]
The earliest description of migraine headaches can be traced to texts dating back thousands of years – detailing how unilateral headaches co-presented with nausea, vomiting, photosensitivity, and auras. These symptoms have led to fruitful hypotheses on the neurological basis of migraine headaches to be primarily a disorder of the trigeminal and vascular systems, with prodromal symptoms linking multiple brainstems, diencephalic, and thalamocortical systems to account for various distorted sensations preceding or accompanying the headaches.[10, 11].
Basic research has helped identify calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as promising therapeutic targets undergoing clinical trials.
Despite migraines being a neurological disorder, their definition is constantly evolving. With high variability in the frequency of occurrence,[13, 14] effective pharmacological treatments, and associated non-headache symptoms, what is currently defined as migraine may be several different diseases with distinct but incompletely understood neuropathology.
Consequently, the study and modeling of migraine in pre-clinical research resemble basic research in psychiatry – most of our understanding stems from modeling specific symptoms and how efficacious treatments impact the physiology and behavior of animals.
Could/Do Animals Experience Migraines?
As all animals, especially rodents in the laboratory, may context-dependently hide pain behavior, cannot vomit or verbally report sensory disturbances, it is extremely difficult to demonstrate if rodents can fully recapitulate various human forms of migraine.
In addition, given the high female prevalence in experiencing migraines and that historically pre-clinical research overwhelmingly favor the use of male-only cohorts, it is unclear how much of our current understanding of migraines is generalizable/directly translatable to the clinic.
Given the current understanding of migraine pathophysiology, there is sufficient inter-species anatomical and physiological homology to assume rodents can experience the symptoms of migraines. It should be noted that given the primary disabling feature of migraines is pain (i.e., headaches), there is some overlap in the use of pain and other headache models in the preclinical studies of migraines.
Until the etiology and pathology of migraines are clearly defined, the interchangeable use of pain and other headache models to study migraines is both necessary and expected in search of better treatments.
Despite the ambiguity of convergence of various types of clinically defined migraine by combinations of symptoms, it is still a disease with a tangible neurological basis. Like all animal models of human disease, there is a limit of how faithful we can recapitulate the pathology seen in humans, and the relevance of symptom-specific findings to the disease itself – this is especially true in migraine as its etiology is unknown; it is not possible to reproduce the primary neuropathology leading to migraine.
As a consequence, most animal models of migraine have focused on the on-demand induction of migraine symptoms (as opposed to the spontaneous, episodic manifestation of symptoms in the human disease) and physiological readouts to quantify symptom severity and the efficacy of drug intervention.
Physiological and Behavioral Readouts in Animal Models of Migraine
A conventional way to measure pain/headache-related response is to record neural activities directly from the neurons responsible for mediating or transmitting such information. Neurophysiological readouts include the assessment of excitation/inhibition to manipulation through firing rates, evoked population responses (evoked potentials), and specific biophysical correlates of dysfunction and drug action.
These readouts depend on the assumption that the chosen recording area is immediately relevant to migraine (headaches) and is essential for delineating brain circuit interactions.
Histochemical Markers of Neural Activation
However, since brain extraction is necessary for this readout, it serves as a “frozen in time” snapshot of brain activation which may be affected by the timing of manipulation and brain extraction.
While the observation of inflammatory processes leading to vasculature changes has driven much of our understanding of pain and headaches in general, more recent data suggest changes in vasculature may be epiphenomenal with little direct relevance to disease etiology and pathology.
Regardless, visual monitoring of blood vessel dilation and constriction as a proxy for inflammation and changes in vessel permeability have been used to gauge the effectiveness of inducing and reversing physiological changes associated with (migraine) headaches.
Allodynia refers to the heightened pain sensitivity where normally non-painful stimuli would cause pain in those affected. It is a characteristic prevalent in migraine sufferers[22, 23] and can be readily reproduced in laboratory animals via almost all of the migraine-inducing methods described here.
Conventionally, manual or electronic Von Frey monofilaments of varying diameters used in pain testing are applied to the periorbital region (to mimic human migraine headache location) on the animal, and head movement away from the filament and/or face washing is deemed to signal that the filament stimulation is noxious.[24, 25, 26]
The measured output is response-based from the first response from increasing stimulation intensity (ascending stimulus), establishing a response threshold (up-down method) and proportion of responses from repetitive applications of various forces (percent response rate).
Of note, thermal allodynia, although not a feature in human migraine, can also be induced in preclinical models. The application of thermal pads adjacent to liquid reward spout in an operant paradigm (orofacial pain assessment device; OPAD), where the reduction of reward consumption can serve as an indicator of thermal allodynia[29, 30] and a surrogate to the more conventional cutaneous/mechanical allodynia.
In addition to audible vocalizations, rodents also use a repertoire of ultrasonic vocalizations (USVs) for communication. Particularly, 22 kHz (and 40 kHz in pups) vocalizations are associated with exposure to aversive stimuli.
This behavioral readout has been leveraged as a measure of pain response, largely in the context of allodynia, in rodent models of migraine,[31, 32] however, several studies suggest USVs cannot serve as a reliable indicator of acute or chronic pain.
Locomotion and General Activity Level
In humans, migraines can be triggered or worsened by physical exercise. Monitoring general activity is a useful addition to other more direct measures of experimental manipulations. Specifically, wheel running, ambulatory measures,[36, 37, 38] and home cage activity monitoring are relevant, but not specific to, migraine pain behavior.
Behavioral Responses to Hypersensitivity to Sensory Inputs
Aversion to light and sometimes sound is also a common symptom in migraine sufferers. Behavioral measures of light/sound avoidance are relevant. They have been used in the context of two-compartment place preference paradigms. The use of experimental migraine-inducing manipulations can increase the avoidance of environments with higher levels of illumination.[41, 36, 42, 43]
However, rodents are naturally aversive to light, so experiments need to be designed to delineate contributions from emotional states (e.g. anxiety) induced by the manipulation, which causes pain and discomfort. As with activity-based measures described above, measuring sensory input (especially light) aversion is perhaps best administered in a battery of behavioral tests.
Changes in Facial Features (Rodent Grimace Scales)
In response to general discomfort to pain, rodents may close/squint their eyes, take back their ears, and bulge their nose/cheek areas. There are established rat and mouse grimace scales (MGC) that have been used to measure migraine induction and effective drug interventions.[46, 47, 45, 48]
Animal Models of Migraine
Ironically, the best model of migraine is perhaps through the administration of known trigger substances to healthy or migraine-suffering human participants. Various compounds such as GTN, sildenafil, histamine, dipyridamole, and PACAP32 can be used to trigger headaches in healthy individuals and migraine attacks for those who suffer from migraines.
Although this model has an excellent face, construct, and predictive validity, the application is largely limited to drug trials as determining biological mechanisms requires unsuitable invasive procedures. Also, it is still common practice to have first demonstrated the safety and efficacy of potential treatments in pre-clinical studies before testing on humans.
In Vitro Models
As mentioned, the location of the pain and compounds that can induce or lessen the headaches provided us with a valuable working hypothesis on how to understand and treat migraines.
Consequently, many in vitro models target specific biophysical mechanisms (e.g., ion channel dynamics relating to cellular excitability) and mechanical vascular changes[50, 51] (e.g., vasodilation), which are presumed to be at work in migraine. These models are high-throughput but lack the complex biological context needed to provide relevant insight for the disease and its effective treatments.
Transgenic Mice: Familial Hemiplegic Migraine Type 1
Familial hemiplegic migraine type 1 (FHM1) is an inherited form of migraine with known mutations to CACNA1A, ATP1A2, SCN1A, and PRRT2 genes. Mouse genetic models have been developed based on the CACNA1A mutation, where S218L mutation has more severe consequences with a higher mortality rate. In contrast, the milder R192Q mutation has been used as a means to study migraines.
This line of mice show altered calcium channel and neuromodulator (acetylcholine) function relating to the reduced threshold for eliciting CSD and the speed of its spread, show spontaneous increases in MGS upon restraint that is reversible by migraine-specific medication, has an impact on CGRP in the trigeminal circuit and show photosensitivity and unilateral head pain but may have limited utility generalizing to more common types of migraine as there are marked genetic and pharmacological differences between people who suffer from non-familial migraines and those who suffer from FHM1[54–55].
Of note, there is also a genetic model of FHM type 2 (FHM2, W887R), which has no apparent clinical phenotype despite lethal homozygosity, displays increase susceptibility to CSD.
Transgenic Mice: Human Receptor Activity-Modifying Protein 1
The human receptor activity-modifying protein 1 (hRAMP1) is an essential, rate-limiting CGRP receptor subunit. While this genetic line is not based on known mutations or pathology in migraine, the rationale for its introduction is based on the observation that CGRP administration can induce migraine in sufferers but not those who never had migraines; then, there must be a disease mechanism which increases migraine sufferers’ sensitivity to CGRP.
By overexpressing hRAMP1 in mice, some migraine-like symptoms such as photosensitivity and allodynia.[56, 57] More extensive characterization is needed to examine how this theory-driven migraine model mimics the human disease and its translational utility – available data indicate that this model does not recapitulate some key symptoms seen in migraine[58, 57]
Transgenic Mice: Casein Kinase 1 Delta
The casein kinase 1d (T44A) mutation is an interesting transgenic model for migraine research, as it is derived from patients suffering from advanced sleep phase syndrome.[59, 60] Initial observations suggested high comorbidity with migraine, and subsequent examination in the CK1d transgenic mice reveal many features commonly found in other models of migraine, namely: decreased threshold for CSD induction and inducible increases in thermal and mechanical pain responses by GTN – particularly in females.
This transgenic model is not a primary model for migraine but appears to recapitulate several migraine-like symptoms to warrant further investigation.
Spontaneous Trigeminal Allodynia in Selectively Bred Rats
Despite the lack of a variety of genetic lines for disease modeling in rats, a selectively bred line of Sprague-Dawley rats (spontaneous trigeminal allodynia; STA rats) show many hallmarks of (migraine) headaches – episodic and trigeminal-related allodynia (but see), sensitivity to sounds, heritability, and susceptibility to externally administered headache triggers. Most importantly, the symptoms displayed by these rats are responsive to medication used to treat migraines.[61, 62]
This model is of particular interest, as the line arose from spontaneous genetic variation and the episodic nature of STA. The trajectory of STA in female rats throughout development closely resembles that of human migraine. However, STA in these rats is not unilaterally localized as in conventional human migraine headaches, and it is currently unknown if STA rats experience aura/exhibit cortical spreading depression.
Modeling Vasculature Changes Mimicking Inflammatory Processes
One of the earliest models for migraine involves using electrical stimulation to directly drive, or indirectly modulate brain physiology. The vasculature-centric approach meant larger animals (including pigs and dogs) have been used in such contexts to “better” match human physiology.
For example, high intensity (up to 3 mA) short pulse (5 ms) square wave stimulation lasting for 5 minutes in the trigeminal ganglion can induce increases in dura mater (but not brain) vascular dilation/permeability subserving inflammatory responses that cause pain.
Although this response can be attenuated by drugs effective for migraines,[64, 65] many other drugs that can reverse vessel permeability do not have any therapeutic value for migraines[66, 67] – the lack of specificity limits the utility of this model. Direct dural stimulation with milder parameters (5 ms, 0.6 mA pulses for 5 minutes) can induce increases in CGRP release and result in dural artery dilation.[68–69]
This can be reversed by migraine-specific drugs but not those impact vasodilation/constriction but have no therapeutic effect on migraines.[68, 70] Other vascular/meningeal nerve targets (e.g., sagittal sinus,[71, 72] middle meningeal artery) can be stimulated to activate headache circuits in the brain not specific to migraine but have shown utility and some specificity in response to drugs used to treat migraines.[71, 74]
Directly Activating Migraine Pain Center
The trigeminal ganglion is central to the pain/headache aspect of migraines. Direct electrical stimulation (usually at ~5 Hz) in anesthetized animals allows the direct activation of pain circuits without inducing inflammatory and vascular responses.[75, 76]
This approach artificially activates the migraine pain circuit in non-behaving animals and does not model other aspects, such as prodromal symptoms, which can be the causes of migraines.
Modeling Aura in Migraine
Cortical spreading depression (CSD) is a neurophysiological phenomenon where a wave of virtually synchronized and complete depolarization slowly propagates across the cortex, followed by a prolonged phase of attenuation in brain electrical activity and reduced blood flow. CSD can be readily induced by electrical, mechanical, or chemical stimulation of the cortex.
There is ample evidence supporting CSD being the physiological mechanism underlying migraine aura.[78, 79] In addition to its physiological relevance to migraine aura to better understand the perceptual phenomena, it also serves as a specific model for drugs effective against migraines with aura but not migraines without[81, 82] – interestingly, the reverse is not the case (i.e., drugs effective against migraines without aura can attenuate CSD in rats[83, 84]).
Chemical Stimulation Model
Much of the early efforts on migraine research have a large overlap with general pain and headache research. Consequently, headache pain pathways, inflammation, and extracranial vascular changes were widely used for migraine research, given headaches are the most debilitating and salient symptom.
Acute application of a concoction of inflammatory substance onto the dura mater to reproduce physiological changes common across headaches/pain has been useful to model the pain aspects of migraine and effective treatments targeting headaches (but not directly migraines). Essentially, inducing an inflammatory response on the meningeal surface is more a model of meningitis, which is not a feature in migraines.
Regardless, this method of migraine (allodynia) induction has shown responsiveness to effective migraine medication and can be applied persistently to result in chronic symptoms and a reduced threshold for GTN-induced exacerbation of allodynia.[37, 25, 38].
As mentioned above, many substances can be used to induce migraine in sufferers or reproduce some aspects of migraine in healthy individuals.
Glyceryl trinitrate (GTN; or nitroglycerin, NTG) is the most used agent to induce migraine in humans and is also effective in activating migraine pain circuits – the same is true for CGRP, which can reproduce photophobia, periorbital allodynia, and spontaneous pain-related behaviors.[88, 36, 48]
There is currently no clear understanding of the etiology of migraines, and the collection of varied symptoms diagnosed as migraines stem from the same underlying pathophysiology.
Given effective treatment options for migraine, per se, has divergent mechanisms and no single treatment shows a clear advantage over others, it is likely “migraine” as they are classified now are at least several biologically distinct entities.
Consequently, animal models of migraine often are reduced to reproduce very specific symptoms or pathophysiology, which may be shared with other types of pain, inflammatory responses, and headaches.
Overall, the STA rat model of migraine may be the “best” model given its derivation from inherent migraine-like traits and the episodic nature of their occurrence. The FHM1 transgenic mouse can also recapitulate multiple aspects of migraine, but the known physiological and genetic differences between familial and more common migraines suggest caution to generalize from the FHM1 model.
Convincing drug and neurophysiology data suggest CSD is the neurological correlate of migraine aura, which may be leveraged to better understand the nature of migraines as a whole.
Overall, migraine is a multi-faceted, multi-stage disease with many possible combinations of symptoms that have benefited from, and would continue to require both symptom-selective reduced models and those with a relevant combination of symptoms mimicking the human condition, due to the lack of clear understanding of what causes migraines.
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