Blockade of 5‐HT3 receptors with granisetron does not affect trigeminothalamic nociceptive transmission in rats: Implication for migraine

Abstract

Summary One way to expand the existing range of anti‐migraine drugs seems to be the search for pharmacological agents with anti‐cephalalgic properties among medicines approved for clinical indications other than migraine. Numerous experimental and clinical data imply that selective serotonin 5‐HT3 receptor antagonists can be considered as potential anti‐migraine agents. Therefore, the objective of our work was to examine the impact of selective 5‐HT3 receptor blockade with granisetron on migraine‐related nociceptive transmission within the spinal trigeminal nucleus (STN) and the ventroposteromedial nucleus of the thalamus (VPM). Using an electrophysiological model of trigemino‐durovascular nociception in anaesthetised male Wistar rats, we evaluated the effects of intravenous administration of granisetron on ongoing firing and dural electrical stimulation‐evoked responses of the spinal trigeminal and thalamic cells. Granisetron did not substantially affect responses of the STN and VPM neurons to electrical stimulation of the dura mater as well as did not cause steady changes in ongoing firing of the spinal trigeminal cells. The results obtained argue against the use of 5‐HT3 receptor antagonists for treating migraine. These data also lead to the conclusion that in the absence of sustained sensitisation of neurons along the trigemino‐thalamo‐cortical pathway the role of 5‐HT3 receptor‐dependent mechanisms in serotonergic modulation of trigeminovascular nociceptive transmission can hardly be considered crucial.

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

“…The 5-HT3 receptors are widely expressed in trigeminovascular system (Kilinc et al, 2017;Barnes et al, 2021;Giniatullin, 2022). Moreover, the controversial role of 5-HT3 receptors in pathophysiology of migraine was previously reported by us and the other groups (Kilinc et al, 2017;Sokolov et al, 2018;Giniatullin, 2022). This may explain different effects of metoclopramide and ondansetron on the parameters associated with migraine in the current study.…”

D2 dopamine receptor‐mediated mechanisms of dopaminergic system modulation in in vivo and in vitro experimental models of migraine

“…The 5‐HT3 receptors are widely expressed in the trigeminovascular system (Barnes et al, 2021; Giniatullin, 2022; Kilinc et al, 2017). Moreover, the controversial role of 5‐HT3 receptors in the pathophysiology of migraine was previously reported by us and the other groups (Giniatullin, 2022; Kilinc et al, 2017; Sokolov et al, 2018). This may explain the different effects of metoclopramide and ondansetron on the parameters associated with migraine in the current study.…”

5‐hydroxytryptamine in migraine: The puzzling role of ionotropic 5‐HT3 receptor in the context of established therapeutic effect of metabotropic 5‐HT1 subtypes

“…Despite the positive effects of these compounds, the conclusion was 'no conclusive evidence with respect to the efficacy of 5-HT 3 receptor antagonists in either the acute or prophylactic treatment of migraine can be derived from clinical studies carried out so far' (Ferrari, 1991). In animal studies in rats, granisetron did not substantially affect trigeminothalamic nociceptive transmission induced by electrical stimulation of the dura mater (Sokolov et al, 2018). It should be noted, however, that it was tested in conditions lacking sensitization of trigeminal neurons which is typical in migraine.…”