loading page

The effects and D2 receptor-mediated mechanisms of dopaminergic system modulation in in-vivo and in-vitro experimental models of migraine
  • Yasemin Baranoglu Kilinc,
  • Ibrahim Torun,
  • Erkan Kilinc
Yasemin Baranoglu Kilinc
Bolu Izzet Baysal State Hospital
Author Profile
Ibrahim Torun
Bolu Abant İzzet Baysal University
Author Profile
Erkan Kilinc
Bolu Abant İzzet Baysal University

Corresponding Author:[email protected]

Author Profile


The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in-vivo and in-vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol, and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal CGRP release in-vitro hemiskull preparations. Mechanical allodynia was tested by von-Frey filaments. CGRP concentrations in trigeminovascular structures and in-vitro superfusates, and c-Fos levels in brainstem were determined by ELISA. Meningeal-mast cells were evaluated with toluidine-blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations, and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in-vitro, while the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated migraine pain by further enchancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migrane like conditions.
02 May 2023Submitted to European Journal of Neuroscience
03 May 2023Submission Checks Completed
03 May 2023Assigned to Editor
03 May 2023Review(s) Completed, Editorial Evaluation Pending
04 May 2023Reviewer(s) Assigned
27 May 2023Editorial Decision: Revise Major
12 Jul 20231st Revision Received
12 Jul 2023Submission Checks Completed
12 Jul 2023Assigned to Editor
12 Jul 2023Review(s) Completed, Editorial Evaluation Pending
12 Jul 2023Reviewer(s) Assigned
20 Jul 2023Editorial Decision: Accept