KCl-induced repetitive cortical spreading depression inhibiting trigeminal neuronal firing is mediated by 5-HT1B/1D and opioid receptors

Weera Supronsinchai; Jan Hoffmann; Simon Akerman; Peter J. Goadsby

doi:10.1177/03331024221112998

KCl-induced repetitive cortical spreading depression inhibiting trigeminal neuronal firing is mediated by 5-HT_1B/1D and opioid receptors

Weera Supronsinchai, Jan Hoffmann, Simon Akerman, Peter J. Goadsby^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Background: We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT_1B/1D and opioid receptors. Methods: Trigeminocervical complex neurons (n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. Results: A sub-population (n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT_1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. Conclusion: The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.

Original language	English
Pages (from-to)	1339-1348
Number of pages	10
Journal	Cephalalgia
Volume	42
Issue number	13
Early online date	13 Jul 2022
DOIs	https://doi.org/10.1177/03331024221112998
Publication status	Published - Nov 2022

Keywords

Cortical spreading depression
migraine
nucleus raphe magnus
opioid
serotonin
trigeminovascular system

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10.1177/03331024221112998

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@article{44ced93a898b41cab0781e3d62fee850,

title = "KCl-induced repetitive cortical spreading depression inhibiting trigeminal neuronal firing is mediated by 5-HT1B/1D and opioid receptors",

abstract = "Background: We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT1B/1D and opioid receptors. Methods: Trigeminocervical complex neurons (n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. Results: A sub-population (n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. Conclusion: The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.",

keywords = "Cortical spreading depression, migraine, nucleus raphe magnus, opioid, serotonin, trigeminovascular system",

author = "Weera Supronsinchai and Jan Hoffmann and Simon Akerman and Goadsby, {Peter J.}",

note = "Funding Information: PJG reports, over the last 36 months, grants and personal fees from Eli-Lilly and Company, grant from Celgene, and personal fees from Abbvie/Allergan, Aeon Biopharma, Amgen, Biohaven Pharmaceuticals Inc., Dr Reddys, Epalex, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma, Teva Pharmaceuticals, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee. Funding Information: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was funded by the Sandler Family Foundation. Publisher Copyright: {\textcopyright} International Headache Society 2022.",

year = "2022",

month = nov,

doi = "10.1177/03331024221112998",

language = "English",

volume = "42",

pages = "1339--1348",

journal = "Cephalalgia",

issn = "0333-1024",

publisher = "Sage Publications",

number = "13",

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TY - JOUR

T1 - KCl-induced repetitive cortical spreading depression inhibiting trigeminal neuronal firing is mediated by 5-HT1B/1D and opioid receptors

AU - Supronsinchai, Weera

AU - Hoffmann, Jan

AU - Akerman, Simon

AU - Goadsby, Peter J.

N1 - Funding Information: PJG reports, over the last 36 months, grants and personal fees from Eli-Lilly and Company, grant from Celgene, and personal fees from Abbvie/Allergan, Aeon Biopharma, Amgen, Biohaven Pharmaceuticals Inc., Dr Reddys, Epalex, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma, Teva Pharmaceuticals, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee. Funding Information: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was funded by the Sandler Family Foundation. Publisher Copyright: © International Headache Society 2022.

PY - 2022/11

Y1 - 2022/11

N2 - Background: We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT1B/1D and opioid receptors. Methods: Trigeminocervical complex neurons (n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. Results: A sub-population (n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. Conclusion: The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.

AB - Background: We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT1B/1D and opioid receptors. Methods: Trigeminocervical complex neurons (n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. Results: A sub-population (n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. Conclusion: The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.

KW - Cortical spreading depression

KW - migraine

KW - nucleus raphe magnus

KW - opioid

KW - serotonin

KW - trigeminovascular system

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DO - 10.1177/03331024221112998

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SN - 0333-1024

VL - 42

SP - 1339

EP - 1348

JO - Cephalalgia

JF - Cephalalgia

IS - 13

ER -

KCl-induced repetitive cortical spreading depression inhibiting trigeminal neuronal firing is mediated by 5-HT_1B/1D and opioid receptors

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