Behavioral and cognitive animal models in headache research

DOI: https://doi.org/10.1186/s10194- 019- 0963- 6

Abstract-Summary Animal models have provided a growing body of information about the pathophysi- ology of headaches and novel therapeutic targets.

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Experiments in awake animals have gained attention as more relevant head-

ache models.

Pain can be assessed in animals using behavioral alterations, which includes

sensory-discriminative, affective-emotional and cognitive aspects.

Mechanical allodynia is usually assessed with von Frey monofilaments and dynamic aesthesiometer, and thermal allodynia can be evaluated with acetone evap- oration test and Hargreaves’ test in animal models.

Anxiety-like behaviors are evaluated with the open-field, elevated plus-maze or

light/dark box tests.

The majority of headache patients complain of cognitive symptoms and migraine

is associated with poor cognitive performance in clinic-based studies.

Only a limited number of animal studies have investigated cognitive aspects of headache disorders, which remains a relatively unexplored aspect of these pathologies.

The headache field has an excellent and growing selection of model systems that

are likely to yield exciting advances in the future.

Extended: Animal models have enhanced our knowledge about the pathophysiol-

ogy of headaches, especially migraine.

Introduction The ophthalmic branch of trigeminal nerve and upper cervical nerves play a crucial role in transmission of pain sensation from intracranial structures and converge on second order neurons in the trigeminal spinal tract (trigeminal nucleus caudalis / trigeminocervical junction).

In relation to the trigeminal innervation pattern, the dura mater is the intracranial

structure sensitive to pain whereas, brain parenchyma is pain insensitive.

Pain and temperature sensation elicited in the dura mater are conducted via Aδ and C fibers of pseudo-unipolar neurons in the trigeminal ganglion to the second order neurons [1, 222].

The aforementioned pathway is called the lateral pain system and related to sen-

sory discriminative aspects of headache perception.

The latter pathway is known as medial pain system and plays a role in the emer-

gence of affective aspects associated with headache [222].

Transmission of noxious signals orthodromically to 2nd order trigeminal neu-

rons, could also activate axonal reflex inducing pain in the referral area.

Pain Behavior Another study using application of inflammatory soup onto the dura of male rats reported increased resting and decreased exploratory behavior for at least 45 min [223].

In a model of single CSD induced by dural N-methyl-D-aspartate (NMDA) application, decreased locomotor activity was also observed, along with other noci- ceptive behaviors but did not reach statistical significance [224].

Contrary to results obtained in other models, a single injection of nitroglycerin

(NTG) in rats increased locomotor activity compared to control animals [225].

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In the same study, rats receiving 3 or 5 administrations of NTG showed signifi-

cantly decreased locomotor activity compared to saline controls [225].

An epidural administration of CGRP induced a dose-dependent decrease in rear- ing behavior of rats in which the animals seized the cage with their front paws [226]. After an epidural injection of CGRP, rats showed significant decrease in facial

grooming within 30 min, but no increase in body grooming was observed [226].

Sensory-Discriminative Aspects Intrathecal injection of CGRP induced plantar mechanical allodynia in mice [227], and monofilament response rates were further enhanced in nestin/hRAMP1 trans- genic mice.

During cold allodynia assessment in the hind paw, acetone is applied alternately three times to each paw and the response to acetone test is scored by the severity of the response (0: no response, 1: quick withdrawal or flick of the paw, 2: prolonged withdrawal or repeated flicking of the paw, 3: repeated flicking of the hind paw and licking of the paw) but the number or duration of nocifensive responses can be also quantified.

In a NTG-induced mouse model of chronic migraine, the duration of withdrawal responses to acetone in the facial region were significantly increased in mice treated with NTG compared to control [228].

In a neuropathic pain model achieved by ligating L5–6 spinal nerves, the effect of percutaneous pulsed radiofrequency (PRF) on mechanical allodynia was evalu- ated and paw withdrawal thresholds were measured via dynamic plantar aesthesi- ometer [229].

Affective and Emotional Aspects Open-field, elevated plus-maze or light/dark box tests are used to evaluate anxiety- like behaviors in animals.

In a chronic migraine animal model, the percentage of open arm entries was significantly lower in chronic migraine group compared to controls which sup- ported increased anxiety-like behavior [230].

In an experimental chronic migraine model induced by intermittent intraperito- neal injection of NTG in which the effect of chronic ghrelin treatment on endoge- nous pituitary adenylate cyclase-activating polypeptide (PACAP) and associated symptoms of migraine was investigated, photophobia and anxiety-like behaviors were determined by the modified EPM and the light/dark box tests [231].

NTG group exhibited anxiety-like behaviors and NTG + ghrelin group displayed

less anxiety-like behaviors in both modified EPM and light/dark box tests [231].

After the conditioning sessions, a 15 min test session is conducted in which the animal is placed in the center with the gates of the both compartments open and the time the animal spends in each compartment is recorded.

Cognitive Assessment Dilekoz and others [232], used the Morris water maze to assess spatial learning and memory in FHM1 mutant mice and wild type (WT) mice and found that the time to reach the hidden platform was similar between WT and homozygous R192Q mice

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during the first training session and gradually decreased in both groups in the fol- lowing sessions.

In two previous studies that used unilateral spared nerve injury (SNI) neuropathy as a model of neuropathic pain, ASST was used evaluate attention, reversal learning and cognitive flexibility and right sided SNI was associated with impaired reversal learning.

There is no preclinical study that used ASST to assess attention, learning and

cognitive flexibility in migraine animal models.

In a study that compared attention and memory in FHM1 mutant mice and WT mice using the novel object recognition test [232], the time spent to explore a novel object compared to a familiar object was comparable between WT and R192Q mice whereas, heterozygous S218 L mice performed worse than WT mice, and homozy- gous S218 L mice performed worse than both WT and R192Q mice.

Behavioral Models of Associated Symptoms Up to 4 administrations of NTG were not sufficient to induce light-aversion in rats exposed to 260 lm, however, after the fifth administration over a 2 week period, the NTG group showed a significant decrease in the time spent in the light chamber compared to the saline group but not the vehicle group [233].

Though, if mice develop enough light-aversion, they might choose to spend more

time in the open arms that are dark rather than in the closed arms that are bright.

Using both assays, repeated administration of NTG in rats induced light-aversion compared to saline-injected animals, as showed by a shorter latency to enter the dark box, a smaller number of transitions during the assay, a decreased time spent in the light, a longer latency to re-enter the light box, an increased time spent in the dark open arms and an increased number of entries in the dark open arms [231].

Conclusion Animal models have enhanced our knowledge about the pathophysiology of head- aches, especially migraine.

Animals subjected to pain stimuli will change their behaviors. Different aspects of pain such as sensory-discriminative, affective-emotional and

cognitive aspects can be assessed with specific behavioral assays.

The open-field, elevated plus-maze or light/dark box tests are used to evaluate anxiety-like behaviors in animals and the forced-swim or tail suspension tests are used to assess depression and anti-depressant activity of medications.

Behavioral and cognitive assays used in headache animal models could provide

new information about pain pathways and novel targets for headache treatment.

Acknowledgement A machine generated summary based on the work of Vuralli, Doga; Wattiez, Anne- Sophie; Russo, Andrew F.; Bolay, Hayrunnisa. 2019 in The Journal of Headache and Pain.

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