2. Academic Validation
  3. CGRP-dependent sensitization of PKC-δ positive neurons in central amygdala mediates chronic migraine

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

  • J Headache Pain. 2022 Dec 12;23(1):157. doi: 10.1186/s10194-022-01531-8.
Tse-Ming Chou 1 2,  Zhung-Fu Lee 3 4,  Shuu-Jiun Wang 1 3 5 6,  Cheng-Chang Lien # 7 8 9,  Shih-Pin Chen # 10 11 12 13 14 15
Affiliations

Affiliations

  • 1 Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 2 Interdisciplinary Neuroscience Program, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan.
  • 3 Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 4 Development, Disease Models and Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 5 College of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 6 Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
  • 7 Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. cclien@nycu.edu.tw.
  • 8 Interdisciplinary Neuroscience Program, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan. cclien@nycu.edu.tw.
  • 9 Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. cclien@nycu.edu.tw.
  • 10 Interdisciplinary Neuroscience Program, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan. chensp1977@gmail.com.
  • 11 Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. chensp1977@gmail.com.
  • 12 College of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. chensp1977@gmail.com.
  • 13 Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, 112, Taiwan. chensp1977@gmail.com.
  • 14 Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. chensp1977@gmail.com.
  • 15 Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, 112, Taiwan. chensp1977@gmail.com.
  • # Contributed equally.
PMID: 36510143 DOI: 10.1186/s10194-022-01531-8
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 CGRP8-37 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.

Keywords

CGRP; Central amygdala; Chronic migraine; PKC-δ; Parabrachial nucleus.

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