The effect of CGRP receptor antagonist on behavior induced by cortical spreading depression

Cortical spreading depression (CSD) which is an important component of migraine pathophysiology is shown to activate trigeminal nucleus caudalis (TNC) and trigger neurogenic inflammation in Dura mater. Today, behavioral alterations due to CSD are unknown. In this study, the effect of CSD on pain and anxiety behavior in awake rats were investigated and compared to effects on subcortical structures. Also, the role of behavioral and cortical activation of CGRP receptor antagonist (MK-8825) after CSD was investigated to understand pain mechanisms.CSD was performed by topical KCl in awake rat and basal pain thresholds to mechanical and cold allodynia were evaluated. Rats were given saline, CGRP receptor antagonist 30 and 100 mg/kg. After CSD induction, spontaneous behavior, ultrasonic vocalization was recorded; anxiety tested by elevated plus maze and mechanical and cold allodynia were evaluated. C-fos immunohistochemistry was performed in brain stem, subcortical and cortical brain areas. After CSD, freezing, grooming, head shake and wet dog shake, head grooming, eating, drinking, yawning, stretching, sleep, maximum speed, turning, sedation and locomotor activity were observed. In CGRP receptor antagonist groups freezing, head and body grooming, sleeping, head shake and wet dog shake were less compared to saline group (p<0,05). Sedation /apathy and related decrease in maximum speed, increase in yawning and stretching, increased mechanical and cold allodynia thresholds were observed in CGRP receptor antagonist groups compared to saline group (p<0,05). Anxiety was higher dose dependently in CGRP receptor antagonist groups (p<0,05). In CGRP receptor antagonist groups, c-fos positive cells were less in TNC dose dependently compared to saline group. c-fos positive cells in ipsilateral cingulate and insular cortex, amygdala and thalamus were present. In thalamus reticular nucleus (TRN), c fos positive cells were less in CGRP receptor antagonist 30 mg/kg group than other groups (p<0,05). No significant difference was found among other thalamic nucleii. In CGRP receptor antagonist 30 mg/kg group, c-fos positive cells were less in TNC and TRN which is consistent, so that TRN was thought to be related to pain.As a result, KCl induced CSD was associated with pain and anxiety behavior and CGRP receptor antagonists dose dependently attenuated pain and related effects. In this study TRN was thought to have an important role in migraine pathophysiology for the first time. CGRP antagonists are effective on pain induced by CSD and further electrophysiological studies to enlighten the role of thalamus in headache are needed.