The influence of metoclopramide on trigeminovascular nociception: possible anti-migraine mechanism of action.
Neuroscience. 2019 Nov 27;:
Authors: Dolgorukova A, Osipchuk AV, Murzina AA, Sokolov AY
Metoclopramide widely used as an abortive migraine therapy due to the advantage of having not only antiemetic, but also analgesic properties. Despite the proven clinical efficacy of metoclopramide in acute migraine, the mechanism of its anti-cephalalgic action has not been entirely elucidated. Taking into account the key role of the trigeminovascular system activation in migraine pathophysiology, we aimed to investigate metoclopramide effects on the excitability of central trigeminovascular neurons and neurogenic dural vasodilation using valid electrophysiological and neurovascular models of trigeminovascular nociception. Extracellular recordings of the activity of second-order dura-sensitive neurons were made in the trigeminocervical complex (TCC) of 16 anaesthetised rats. Cumulative metoclopramide infusion (three steps in 30 min intervals, 5 mg/kg i.v. per step, n=8) significantly and dose-dependently suppressed both ongoing firing of the TCC neurons and their responses to dural electrical stimulation, maximally to 30%[0%-49%] (median[Q1-Q3]) and 4%[0%- 30%] of the initial level, respectively (both p=0.001, compared to saline (n=8)). By contrast, the neurogenic dural vasodilation studied in a separate group of 12 rats was not significantly affected by cumulative infusion of metoclopramide (5 mg/kg i.v. per step, n=6) compared to both baseline values and the vehicle group (n=6) (all p>0.05). These results provide evidence that metoclopramide is unable to affect the peripheral response to trigeminovascular activation, but it does suppress the central response, which is highly predictive of anti-migraine action. Thus, here we show the neurophysiological mechanism underlying the therapeutic efficacy of metoclopramide in migraine.
PMID: 31785356 [PubMed – as supplied by publisher]