The effects and D2 receptor-mediated mechanisms of dopaminergic system
modulation in in-vivo and in-vitro experimental models of migraine
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.