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CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior

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  • Aslı Filiz
  • Nermin Tepe
  • Sajedeh Eftekhari
  • H Evren Boran
  • Ergin Dilekoz
  • Lars Edvinsson
  • Hayrunnisa Bolay
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Background and objective The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. Methods CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. Results MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. Conclusion CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.

Original languageEnglish
JournalCephalalgia : an international journal of headache
Volume39
Issue number3
Pages (from-to)354-365
Number of pages12
ISSN0333-1024
DOIs
Publication statusPublished - 1 Mar 2019
Externally publishedYes

    Research areas

  • Journal Article, Migraine, pain behavior, thalamic reticular nucleus, cortical spreading depression, CGRP

ID: 52342274