Involvement of kainate glutamate receptors in the modulation of neuronal transmission in brain areas involved in migraine pathophysiology.
Doctoral thesis, UCL (University College London).
Migraine pathophysiology is thought to involve activation of the trigeminal fibres which innervate dural structures. The nociceptive inflow from the meninges is relayed to the trigeminocervical complex (TCC), before ascending to higher brain areas, including the thalamus. Glutamate is implicated in the transmission of the nociceptive information and thus an increased understanding of the nature and effects of glutamate receptors activation has major implications in migraine pathophysiology and treatment. Here the role of kainate receptors, a member of the ionotropic glutamate receptors subfamily, was investigated in relaying sensory information upon activation of the trigeminovascular system. In order to study the role of kainate receptors on the periphery, we used the neurogenic dural vasodilation (NDV) model, in which electrical stimulation of the dura mater causes reproducible vasodilation, due to calcitonic gene-related peptide (CGRP) release. In this set of experiments kainate receptor activation but not blockade was effective in inhibiting NDV. Vasodilation induced by systemic administration of CGRP was not changed by administration of a kainate receptor agonist. In the TCC, local application by microiontophoresis of a selective kainate receptor antagonist on second order neurons which were excited by meningeal electrical stimulation, caused dual effects; 50% of the neurons tested were inhibited, whereas in a second subpopulation, activation in response to meningeal stimulation was facilitated. However, in all neurons tested, post-synaptic activation in response to kainate receptor agonists application was selectively inhibited. Microiontophoretic ejection of a kainate receptor antagonist in the ventroposteromedial thalamus (VPM) was able to inhibit cell firing in response to dural stimulation, as well as post-synaptic firing in response to kainate receptor activation. Both effects were reversed when the kainate receptor antagonist was co-ejected with a 5-HT1B receptor antagonist. We also carried electrophysiology studies in both the TCC and the VPM nucleus in order to compare the effects of the clinically active kainate receptor antagonist LY466195. Systemic and local application of LY466195 was able to inhibit cell firing in response to dura mater stimulation in both the TCC and VPM nucleus. Moreover, further to the kainate binding, a significant action of the compound on N-methyl-Daspartate receptors was observed.
|Title:||Involvement of kainate glutamate receptors in the modulation of neuronal transmission in brain areas involved in migraine pathophysiology|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience|
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