Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain

• Published in: Neuropharmacology 2017-04, Vol.116, p.160-173
• Main Authors: Kilinc, Erkan, Guerrero-Toro, Cindy, Zakharov, Andrey, Vitale, Carmela, Gubert-Olive, Max, Koroleva, Ksenia, Timonina, Arina, Luz, Liliana L., Shelukhina, Irina, Giniatullina, Raisa, Tore, Fatma, Safronov, Boris V., Giniatullin, Rashid
• Format: Article
• Language: English
• Subjects: 5-HT3 receptor; Action Potentials - drug effects; Action Potentials - physiology; Animals; Calcitonin Gene-Related Peptide - metabolism; Calcium - metabolism; Cations, Divalent - metabolism; Female; Male; Meninges; Migraine; Migraine Disorders - metabolism; Neurons, Afferent - cytology; Neurons, Afferent - drug effects; Neurons, Afferent - metabolism; Nociception - drug effects; Nociception - physiology; Patch-Clamp Techniques; Rats, Wistar; Receptors, Serotonin - metabolism; Serotonin; Serotonin - metabolism; Serotonin Agents - pharmacology; Spike; Tissue Culture Techniques; Trigeminal nerve; Trigeminal Nerve - cytology; Trigeminal Nerve - drug effects; Trigeminal Nerve - metabolism; TRPV Cation Channels - metabolism; Voltage-Sensitive Dye Imaging
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.12.024

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. •5-HT induced a robust nociceptive activity in peripheral nerve terminals in meninges.•5-HT3 receptors contributed to pro-nociceptive action 5-HT and CGRP release.•Cluster analysis revealed fibers with remarkably long-lasting firing activity.•In contrast to periphery, 5-HT inhibited central nerve terminals of nociceptors.