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The Journal of Headache and Pain

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Open Access 01-12-2022 | Migraine | Research

CGRP-dependent sensitization of PKC-δ positive neurons in central amygdala mediates chronic migraine

Authors: Tse-Ming Chou, Zhung-Fu Lee, Shuu-Jiun Wang, Cheng-Chang Lien, Shih-Pin Chen

Published in: The Journal of Headache and Pain | Issue 1/2022

Abstract

Background

To investigate specific brain regions and neural circuits that are responsible for migraine chronification.

Methods

We established a mouse model of chronic migraine with intermittent injections of clinically-relevant dose of nitroglycerin (0.1 mg/kg for 9 days) and validated the model with cephalic and extracephalic mechanical sensitivity, calcitonin gene-related peptide (CGRP) expression in trigeminal ganglion, and responsiveness to sumatriptan or central CGRP blockade. We explored the neurons that were sensitized along with migraine chronification and investigated their roles on migraine phenotypes with chemogenetics.

Results

After repetitive nitroglycerin injections, mice displayed sustained supraorbital and hind paw mechanical hyperalgesia, which lasted beyond discontinuation of nitroglycerin infusion and could be transiently reversed by sumatriptan. The CGRP expression in trigeminal ganglion was also upregulated. We found the pERK positive cells were significantly increased in the central nucleus of the amygdala (CeA), and these sensitized cells in the CeA were predominantly protein kinase C-delta (PKC-δ) positive neurons co-expressing CGRP receptors. Remarkably, blockade of the parabrachial nucleus (PBN)-CeA CGRP neurotransmission by CGRP_8–37 microinjection to the CeA attenuated the sustained cephalic and extracephalic mechanical hyperalgesia. Furthermore, chemogenetic silencing of the sensitized CeA PKC-δ positive neurons reversed the mechanical hyperalgesia and CGRP expression in the trigeminal ganglion. In contrast, repetitive chemogenetic activation of the CeA PKC-δ positive neurons recapitulated chronic migraine-like phenotypes in naïve mice.

Conclusions

Our data suggest that CeA PKC-δ positive neurons innervated by PBN CGRP positive neurons might contribute to the chronification of migraine, which may serve as future therapeutic targets for chronic migraine.

Graphical Abstract

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Title: CGRP-dependent sensitization of PKC-δ positive neurons in central amygdala mediates chronic migraine
Authors: Tse-Ming Chou
Zhung-Fu Lee
Shuu-Jiun Wang
Cheng-Chang Lien
Shih-Pin Chen
Publication date: 01-12-2022
Publisher: Springer Milan
Keywords: Migraine
Nitroglycerin
Sumatriptan
Published in: The Journal of Headache and Pain / Issue 1/2022
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-022-01531-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

CGRP-dependent sensitization of PKC-δ positive neurons in central amygdala mediates chronic migraine

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

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