Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain
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 sugges...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-01-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/3/1529 |
| _version_ | 1797487360005373952 |
|---|---|
| author | Cindy Guerrero-Toro Kseniia Koroleva Elizaveta Ermakova Oleg Gafurov Polina Abushik Pasi Tavi Guzel Sitdikova Rashid Giniatullin |
| author_facet | Cindy Guerrero-Toro Kseniia Koroleva Elizaveta Ermakova Oleg Gafurov Polina Abushik Pasi Tavi Guzel Sitdikova Rashid Giniatullin |
| author_sort | Cindy Guerrero-Toro |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T23:46:30Z |
| format | Article |
| id | doaj.art-2ba64546ea774b60b2a67aa4a16e6afe |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:46:30Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2ba64546ea774b60b2a67aa4a16e6afe2023-11-23T16:42:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233152910.3390/ijms23031529Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine PainCindy Guerrero-Toro0Kseniia Koroleva1Elizaveta Ermakova2Oleg Gafurov3Polina Abushik4Pasi Tavi5Guzel Sitdikova6Rashid Giniatullin7A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandDepartment of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, RussiaDepartment of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, RussiaA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandDepartment of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, RussiaA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandThe 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.https://www.mdpi.com/1422-0067/23/3/1529glutamatemigraineNMDACGRPtrigeminal gangliatrigeminal nerve |
| spellingShingle | Cindy Guerrero-Toro Kseniia Koroleva Elizaveta Ermakova Oleg Gafurov Polina Abushik Pasi Tavi Guzel Sitdikova Rashid Giniatullin Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain International Journal of Molecular Sciences glutamate migraine NMDA CGRP trigeminal ganglia trigeminal nerve |
| title | Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain |
| title_full | Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain |
| title_fullStr | Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain |
| title_full_unstemmed | Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain |
| title_short | Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain |
| title_sort | testing the role of glutamate nmda receptors in peripheral trigeminal nociception implicated in migraine pain |
| topic | glutamate migraine NMDA CGRP trigeminal ganglia trigeminal nerve |
| url | https://www.mdpi.com/1422-0067/23/3/1529 |
| work_keys_str_mv | AT cindyguerrerotoro testingtheroleofglutamatenmdareceptorsinperipheraltrigeminalnociceptionimplicatedinmigrainepain AT kseniiakoroleva testingtheroleofglutamatenmdareceptorsinperipheraltrigeminalnociceptionimplicatedinmigrainepain AT elizavetaermakova testingtheroleofglutamatenmdareceptorsinperipheraltrigeminalnociceptionimplicatedinmigrainepain AT oleggafurov testingtheroleofglutamatenmdareceptorsinperipheraltrigeminalnociceptionimplicatedinmigrainepain AT polinaabushik testingtheroleofglutamatenmdareceptorsinperipheraltrigeminalnociceptionimplicatedinmigrainepain AT pasitavi testingtheroleofglutamatenmdareceptorsinperipheraltrigeminalnociceptionimplicatedinmigrainepain AT guzelsitdikova testingtheroleofglutamatenmdareceptorsinperipheraltrigeminalnociceptionimplicatedinmigrainepain AT rashidginiatullin testingtheroleofglutamatenmdareceptorsinperipheraltrigeminalnociceptionimplicatedinmigrainepain |