C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

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Edvinsson, Jacob C.A.University of Copenhagen,Copenhagen University Hospital (author)

C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

Article/chapterEnglish2019

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2019-11-12
Springer Science and Business Media LLC,2019

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LIBRIS-ID:oai:lup.lub.lu.se:89caebcc-3f70-4f3a-b245-64b731a5f56d
https://lup.lub.lu.se/record/89caebcc-3f70-4f3a-b245-64b731a5f56dURI
https://doi.org/10.1186/s10194-019-1055-3DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype
Subject category:ref swepub-contenttype

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BACKGROUND: Monoclonal antibodies (mAbs) towards CGRP or the CGRP receptor show good prophylactic antimigraine efficacy. However, their site of action is still elusive. Due to lack of passage of mAbs across the blood-brain barrier the trigeminal system has been suggested a possible site of action because it lacks blood-brain barrier and hence is available to circulating molecules. The trigeminal ganglion (TG) harbors two types of neurons; half of which store CGRP and the rest that express CGRP receptor elements (CLR/RAMP1). METHODS: With specific immunohistochemistry methods, we demonstrated the localization of CGRP, CLR, RAMP1, and their locations related to expression of the paranodal marker contactin-associated protein 1 (CASPR). Furthermore, we studied functional CGRP release separately from the neuron soma and the part with only nerve fibers of the trigeminal ganglion, using an enzyme-linked immunosorbent assay. RESULTS: Antibodies towards CGRP and CLR/RAMP1 bind to two different populations of neurons in the TG and are found in the C- and the myelinated Aδ-fibers, respectively, within the dura mater and in trigeminal ganglion (TG). CASPR staining revealed paranodal areas of the different myelinated fibers inhabiting the TG and dura mater. Double immunostaining with CASPR and RAMP1 or the functional CGRP receptor antibody (AA58) revealed co-localization of the two peptides in the paranodal region which suggests the presence of the CGRP-receptor. Double immunostaining with CGRP and CASPR revealed that thin C-fibers have CGRP-positive boutons which often localize in close proximity to the nodal areas of the CGRP-receptor positive Aδ-fibers. These boutons are pearl-like synaptic structures, and we show CGRP release from fibers dissociated from their neuronal bodies. In addition, we found that adjacent to the CGRP receptor localization in the node of Ranvier there was PKA immunoreactivity (kinase stimulated by cAMP), providing structural possibility to modify conduction activity within the Aδ-fibers. CONCLUSION: We observed a close relationship between the CGRP containing C-fibers and the Aδ-fibers containing the CGRP-receptor elements, suggesting a point of axon-axon interaction for the released CGRP and a site of action for gepants and the novel mAbs to alleviate migraine.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Neurologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Neurology hsv//eng
Aδ-fibers
C-fibers
CASPR
CGRP
Node of Ranvier,
Trigeminal ganglion

Added entries (persons, corporate bodies, meetings, titles ...)

Warfvinge, KarinLund University,Lunds universitet,Medicin, Lund,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Medicine, Lund,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Copenhagen University Hospital(Swepub:lu)oft-kwa (author)
Krause, Diana N.Lund University,Lunds universitet,Experimentell kärlforskning,Forskargrupper vid Lunds universitet,Experimental Vascular Research,Lund University Research Groups,University of California, Irvine(Swepub:lu)med-dku (author)
Blixt, Frank W.University of Texas(Swepub:lu)med-fbl (author)
Sheykhzade, MajidUniversity of Copenhagen (author)
Edvinsson, LarsLund University,Lunds universitet,Experimentell kärlforskning,Forskargrupper vid Lunds universitet,Experimental Vascular Research,Lund University Research Groups,Copenhagen University Hospital(Swepub:lu)med-led (author)
Haanes, Kristian A.Copenhagen University Hospital (author)
University of CopenhagenCopenhagen University Hospital (creator_code:org_t)

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In:Journal of Headache and Pain: Springer Science and Business Media LLC20:11129-23691129-2377

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