Does single cortical spreading depression elicit pain behaviour in freely moving rats?
BACKGROUND
Behavioural animal studies are critical, particularly to translate results to human beings. Cortical spreading depression (CSD) has been implicated in migraine pathogenesis. We aimed to investigate the effects of CSD on the behaviour of freely moving rats, since available CSD models do not include awake animals.


METHODS
We developed a new model to induce single CSD by applying topical N-methyl-D-aspartate (NMDA) and employed a combination of an automated behavioural analysis system, video camera and ultrasonic vocalisation (USV) calls for the first time. Electrocorticograms were also studied during CSD in freely moving rats. Behaviour associated with cephalic pain was assessed in a group of rats that received sumatriptan. Cortical c-fos immunoreactivity was performed in order to confirm CSD.


RESULTS
NMDA induced single CSD in ipsilateral cortex, evoked freezing behaviour (P < 0.01) and increased the number of wet dog shakes (WDS; P < 0.01). Grooming, locomotion, eating, drinking, and circling were not significantly altered among groups. Ultrasonic vocalisations compatible with pain calls (22-27 kHz) were only detected in 3 out of 25 rats. Sumatriptan did not significantly reduce the freezing behaviour. CSD induced significant c-fos expression in ipsilateral cerebral cortex and amygdala (P < 0.01).


CONCLUSIONS
CSD induces freezing behaviour by invoking anxiety/fear via amygdala activation in freely-moving rats. Single CSD is unlikely to lead to severe pain in freely-moving rats, though the development of mild or vague pain cannot be excluded. The relevance of rat behavioural responses triggered by CSD to migraine symptoms in humans needs further evaluation.
Akcali
Didem
D
Gazi University Faculty of Medicine, Neuropsychiatry Centre, Ankara, Turkey.
Sayin
Aslihan
A
Sara
Yildirim
Y
Bolay
Hayrunnisa
H
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology*; D004569:Electroencephalography; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D007150:Immunohistochemistry; D008297:Male; D008881:Migraine Disorders / Q000378:metabolism / Q000503:physiopathology*; D009068:Movement; D016202:N-Methylaspartate / Q000633:toxicity; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014828:Vocalization, Animal / Q000187:drug effects / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D016760:Proto-Oncogene Proteins c-fos; D016202:N-Methylaspartate