C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system.
Animals
Axons
Calcitonin Gene-Related Peptide
/ metabolism
Calcitonin Gene-Related Peptide Receptor Antagonists
/ metabolism
Dura Mater
/ metabolism
Immunohistochemistry
Male
Migraine Disorders
/ physiopathology
Nerve Fibers
/ metabolism
Neurons
/ metabolism
Ranvier's Nodes
/ metabolism
Rats
Rats, Sprague-Dawley
Receptor Activity-Modifying Protein 1
/ metabolism
Receptors, Calcitonin Gene-Related Peptide
/ metabolism
Signal Transduction
Trigeminal Ganglion
/ metabolism
Aδ-fibers
C-fibers
CASPR
CGRP
Node of Ranvier,
Trigeminal ganglion
Journal
The journal of headache and pain
ISSN: 1129-2377
Titre abrégé: J Headache Pain
Pays: England
ID NLM: 100940562
Informations de publication
Date de publication:
12 Nov 2019
12 Nov 2019
Historique:
received:
05
10
2019
accepted:
29
10
2019
entrez:
14
11
2019
pubmed:
14
11
2019
medline:
26
2
2020
Statut:
epublish
Résumé
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). 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 31718551
doi: 10.1186/s10194-019-1055-3
pii: 10.1186/s10194-019-1055-3
pmc: PMC6852900
doi:
Substances chimiques
Calcitonin Gene-Related Peptide Receptor Antagonists
0
Receptor Activity-Modifying Protein 1
0
Receptors, Calcitonin Gene-Related Peptide
0
Calcitonin Gene-Related Peptide
JHB2QIZ69Z
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
105Subventions
Organisme : Lundbeckfonden
ID : R59-A5404
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