title: Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain.
abstract: Serotonergic mechanisms play a central role in migraine pathology. However, the region-specific effects of serotonin (5-HT) mediated via multiple types of receptors in the nociceptive system are poorly understood. Using extracellular and patch-clamp recordings, we studied the action of 5-HT on the excitability of peripheral and central terminals of trigeminal afferents. 5-HT evoked long-lasting TTX-sensitive firing in the peripheral terminals of meningeal afferents, the origin site of migraine pain. Cluster analysis revealed that in majority of nociceptive fibers 5-HT induced either transient or persistent spiking activity with prevailing delta and theta rhythms. The 5-HT3-receptor antagonist MDL-72222 or 5-HT1B/D-receptor antagonist GR127935 largely reduced, but their combination completely prevented the excitatory pro-nociceptive action of 5-HT. The 5-HT3 agonist mCPBG activated spikes in MDL-72222-dependent manner but the 5HT-1 receptor agonist sumatriptan did not affect the nociceptive firing. 5-HT also triggered peripheral CGRP release in meninges, which was blocked by MDL-72222.5-HT evoked fast membrane currents and Ca2+transients in a fraction of trigeminal neurons. Immunohistochemistry showed expression of 5-HT3A receptors in fibers innervating meninges. Endogenous release of 5-HT from degranulated mast cells increased nociceptive firing. Low pH but not histamine strongly activated firing. 5-HT reduced monosynaptic inputs from trigeminal Aδ- and C-afferents to the upper cervical lamina I neurons and this effect was blocked by MDL-72222. Consistent with central inhibitory effect, 5-HT reduced CGRP release in the brainstem slices. In conclusion, 5-HT evokes powerful pro-nociceptive peripheral and anti-nociceptive central effects in trigeminal system transmitting migraine pain.
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland; Abant Izzet Baysal University, Medical Faculty, Department of Physiology, 14280, Bolu, Turkey. Electronic address: e_kilinc_27@hotmail.com.
authors.forename: Erkan
authors.initials: E
authors.lastname: Kilinc
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. Electronic address: cguerreroto@gmail.com.
authors.forename: Cindy
authors.initials: C
authors.lastname: Guerrero-Toro
authors.affiliation: Laboratory of Neurobiology, Kazan Federal University, 420008, Kazan, Russia; Department of Physiology, Kazan State Medical University, 420012, Kazan, Russia. Electronic address: AnVZaharov@kpfu.ru.
authors.forename: Andrey
authors.initials: A
authors.lastname: Zakharov
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. Electronic address: cvitale42@gmail.com.
authors.forename: Carmela
authors.initials: C
authors.lastname: Vitale
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. Electronic address: max.gubert@e-campus.uab.cat.
authors.forename: Max
authors.initials: M
authors.lastname: Gubert-Olive
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland; Laboratory of Neurobiology, Kazan Federal University, 420008, Kazan, Russia.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Koroleva
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland.
authors.forename: Arina
authors.initials: A
authors.lastname: Timonina
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal. Electronic address: laracho@ibmc.up.pt.
authors.forename: Liliana L
authors.initials: LL
authors.lastname: Luz
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Moscow, Russia. Electronic address: ner-neri@yandex.ru.
authors.forename: Irina
authors.initials: I
authors.lastname: Shelukhina
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. Electronic address: raisa.giniatullina@uef.fi.
authors.forename: Raisa
authors.initials: R
authors.lastname: Giniatullina
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland; Biruni University, School of Medicine, 34010, Istanbul, Turkey. Electronic address: torefatma@gmail.com.
authors.forename: Fatma
authors.initials: F
authors.lastname: Tore
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Neuronal Networks Group, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135, Porto, Portugal. Electronic address: safronov@ibmc.up.pt.
authors.forename: Boris V
authors.initials: BV
authors.lastname: Safronov
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland; Laboratory of Neurobiology, Kazan Federal University, 420008, Kazan, Russia. Electronic address: rashid.giniatullin@uef.fi.
authors.forename: Rashid
authors.initials: R
authors.lastname: Giniatullin
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D005260:Female; D008297:Male; D008578:Meninges; D008881:Migraine Disorders / Q000378:metabolism; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism; D046509:Tissue Culture Techniques; D014276:Trigeminal Nerve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D002413:Cations, Divalent; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D012701:Serotonin; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium
keywords: 5-HT3 receptor; Migraine; Serotonin; Spike; Trigeminal nerve