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

Filiz A., Tepe N., Eftekhari S., BORAN H. E., DİLEKÖZ E., Edvinsson L., ...More

CEPHALALGIA, vol.39, no.3, pp.354-365, 2019 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 39 Issue: 3
  • Publication Date: 2019
  • Doi Number: 10.1177/0333102417735845
  • Journal Name: CEPHALALGIA
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.354-365
  • Keywords: Migraine, cortical spreading depression, CGRP, pain behavior, thalamic reticular nucleus, GENE-RELATED PEPTIDE, THALAMIC RETICULAR NUCLEUS, CONTROLLED-TRIAL, TELCAGEPANT, NOCICEPTION, ALLODYNIA, RESPONSES, ANXIETY, RATS
  • Gazi University Affiliated: Yes


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.