Tags

Type your tag names separated by a space and hit enter

Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain.
Neuropharmacology 2017; 116:160-173N

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+Show Affiliations

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.A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. Electronic address: cguerreroto@gmail.com.Laboratory of Neurobiology, Kazan Federal University, 420008, Kazan, Russia; Department of Physiology, Kazan State Medical University, 420012, Kazan, Russia. Electronic address: AnVZaharov@kpfu.ru.A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. Electronic address: cvitale42@gmail.com.A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. Electronic address: max.gubert@e-campus.uab.cat.A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland; Laboratory of Neurobiology, Kazan Federal University, 420008, Kazan, Russia.A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland.Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal. Electronic address: laracho@ibmc.up.pt.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.A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. Electronic address: raisa.giniatullina@uef.fi.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.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.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28025094

Citation

Kilinc, Erkan, et al. "Serotonergic Mechanisms of Trigeminal Meningeal Nociception: Implications for Migraine Pain." Neuropharmacology, vol. 116, 2017, pp. 160-173.
Kilinc E, Guerrero-Toro C, Zakharov A, et al. Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain. Neuropharmacology. 2017;116:160-173.
Kilinc, E., Guerrero-Toro, C., Zakharov, A., Vitale, C., Gubert-Olive, M., Koroleva, K., ... Giniatullin, R. (2017). Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain. Neuropharmacology, 116, pp. 160-173. doi:10.1016/j.neuropharm.2016.12.024.
Kilinc E, et al. Serotonergic Mechanisms of Trigeminal Meningeal Nociception: Implications for Migraine Pain. Neuropharmacology. 2017;116:160-173. PubMed PMID: 28025094.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain. AU - Kilinc,Erkan, AU - Guerrero-Toro,Cindy, AU - Zakharov,Andrey, AU - Vitale,Carmela, AU - Gubert-Olive,Max, AU - Koroleva,Ksenia, AU - Timonina,Arina, AU - Luz,Liliana L, AU - Shelukhina,Irina, AU - Giniatullina,Raisa, AU - Tore,Fatma, AU - Safronov,Boris V, AU - Giniatullin,Rashid, Y1 - 2016/12/23/ PY - 2016/04/15/received PY - 2016/12/02/revised PY - 2016/12/22/accepted PY - 2016/12/28/pubmed PY - 2018/5/10/medline PY - 2016/12/28/entrez KW - 5-HT3 receptor KW - Migraine KW - Serotonin KW - Spike KW - Trigeminal nerve SP - 160 EP - 173 JF - Neuropharmacology JO - Neuropharmacology VL - 116 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/28025094/Serotonergic_mechanisms_of_trigeminal_meningeal_nociception:_Implications_for_migraine_pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(16)30589-5 DB - PRIME DP - Unbound Medicine ER -