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. 2022 Nov;42(13):1339-1348.
doi: 10.1177/03331024221112998. Epub 2022 Jul 13.

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

Weera Supronsinchai  1 , Jan Hoffmann  2 , Simon Akerman  3 , Peter J Goadsby  2   4
Affiliations

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

Weera Supronsinchai et al. Cephalalgia. 2022 Nov.

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.

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Conflict of interest statement

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:

WS has nothing to report.

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.

JH reports honoraria for consulting activities and/or serving on advisory boards from Allergan, Autonomic Technologies Inc., Chordate Medical AB, Eli Lilly, Hormosan Pharma, Novartis and Teva. He received personal fees for Medico-Legal work as well as from Sage Publishing, Springer Healthcare and Quintessence Publishing. All these activities are unrelated to the submitted work.

SA reports personal fees from Allergan, Amgen, GSK, Novartis, and A&O unrelated to the submitted work.

Figures

Figure 1.
Figure 1.
(a) The locations of recording site in the trigeminocervical complex (TCC) at the level of C1 responding to electrical stimulation of afferents from the middle meningeal artery, its branches, and periarterial dura as indicated by thermoelectrical lesions. The locations were reconstructed from unaffected trigeminal cell firing animals (closed circle) or from inhibitory trigeminal cell firing animals (open circles) and (b) Example of a thermoelectrical lesion site in the TCC (arrow).
Figure 2.
Figure 2.
Post-stimulus histograms of neuronal responses to electrical stimulation of the dura mater around the middle meningeal artery (MMA) for two distinct outcomes A/B and C/D. (a) Baseline response before CSD; (b) 20 minutes after CSD. The units with A-fiber input are not affected by KCl induced CSD. (c) Baseline response before CSD and (d) 20 minutes after CSD. The units with A-fiber input are inhibited by KCl-induced CSD. Units firing over 20 sweeps of 50 ms are shown.
Figure 3.
Figure 3.
Effect of cortical spreading depression induced by 3 mg KCl on post-stimulated histogram and spontaneous background activity in response to electrical stimulation of afferents from the middle meningeal artery, its branches, and periarterial dura. (a) Total 30 neurons, nine out of the 30 neurons showed an average inhibition of TCC neuron firing from baseline and (b) The spontaneous background activity was unaltered. *P < 0.05 significance compared with baseline. Meningeal A-delta fiber refers to trigeminocervical neurons receiving input from a dural afferent.
Figure 4.
Figure 4.
Effect of intravenous injection of GR127935 and naloxone on KCl-induced inhibition of trigeminal neuron firing in response to electrical stimulation of afferents from the middle meningeal artery, its branches, and periarterial dura. Intravenous injection of (a) GR127935 (3 mg/kg) and (b) naloxone (1.5 mg/kg) had significant reverse the inhibition of trigeminal neurons firing 5 minute after injection compared with inhibition of trigeminal neuron firing. (c) and (d) Spontaneous background activity had no significant different to baseline. *P < 0.05 significance compared with inhibitory trigeminal neuron firing. Meningeal A-delta fiber refers to trigeminocervical neurons receiving input from a dural afferent.
Figure 5.
Figure 5.
Effect of microinjection of lidocaine and muscimol into the NRM on KCl-induced inhibition of trigeminal neuron firing in response to electrical stimulation of afferents from the middle meningeal artery, its branches, and periarterial dura. (a) This inhibition was unaffected by microinjection of (a) lidocaine (2%, 100 nl) and (b) muscimol (100 mM, 100 nl) into the NRM. *P < 0.05 significance compared with  inhibitory trigeminal neuron firing. (c) and (d) Spontaneous background activity had no significant different to baseline. #P < 0.05 significance compared baseline. #P < 0.05 significance compared with unaffected trigeminal neuron firing. Meningeal A-delta fiber refers to trigeminocervical neurons receiving input from a dural afferent.
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