Abstract
The pro-nociceptive role of glutamate in the CNS in migraine pathophysiology is well established. Glutamate, released from trigeminal afferents, activates second order nociceptive neurons in the brainstem. However, the function of peripheral glutamate receptors in the trigeminovascular system suggested as the origin site for migraine pain, is less known. In the current project, we used calcium imaging and patch clamp recordings from trigeminal ganglion (TG) neurons, immunolabelling, CGRP assay and direct electrophysiological recordings from rat meningeal afferents to investigate the role of glutamate in trigeminal nociception. Glutamate, aspartate, and, to a lesser extent, NMDA under free-magnesium conditions, evoked calcium transients in a fraction of isolated TG neurons, indicating functional expression of NMDA receptors. The fraction of NMDA sensitive neurons was increased by the migraine mediator CGRP. NMDA also activated slowly desensitizing currents in 37% of TG neurons. However, neither glutamate nor NMDA changed the level of extracellular CGRP. TG neurons expressed both GluN2A and GluN2B subunits of NMDA receptors. In addition, after removal of magnesium, NMDA activated persistent spiking activity in a fraction of trigeminal nerve fibers in meninges. Thus, glutamate activates NMDA receptors in somas of TG neurons and their meningeal nerve terminals in magnesium-dependent manner. These findings suggest that peripherally released glutamate can promote excitation of meningeal afferents implicated in generation of migraine pain in conditions of inherited or acquired reduced magnesium blockage of NMDA channels and support the usage of magnesium supplements in migraine.
Highlights
Introduction published maps and institutional affilMigraine is a common and complex neurological disorder, which neurochemical mechanisms leading to a severe headache are largely unknown [1,2]
We tested at the level of single cells, whether trigeminal ganglion (TG) neurons express functional glutamate receptors
Using the broad-spectrum glutamate receptor agonists, glutamate and aspartate, we showed here with a calcium imaging approach that the essential fraction of TG neurons responds to these endogenous agonists
Summary
Migraine is a common and complex neurological disorder, which neurochemical mechanisms leading to a severe headache are largely unknown [1,2]. A major excitatory neurotransmitter in the central nervous system [3], mediates the synaptic transmission from the primary afferents to the second order nociceptive neurons in the brainstem [4]. Glutamate plays a key role in cortical hyperexcitability in familial type migraine [5]. Peripheral nerves release glutamate in response to thermal or electrical stimulation [6,7]. The role of glutamate in peripheral mechanisms of migraine, in particular, in the generation of nociceptive pain signals in meninges, which are supposed to be origin site for migraine pian, remains poorly understood. Glutamate mediates its physiological functions acting via ionotropic α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) or kainate receptors iations
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
