• Antonina Dolgorukova, Anastasiia V Osipchuk, Anna A Murzina, and Alexey Y Sokolov.
• Department of Neuropharmacology, Valdman Institute of Pharmacology, Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6-8, 197022 Saint Petersburg, Russia. Electronic address: an.dolgorukova@gmail.com.
• Neuroscience. 2020 Jan 15; 425: 123-133.

AbstractMetoclopramide is 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.Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

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