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C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system.
J Headache Pain. 2019 Nov 12; 20(1):105.JH

Abstract

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.

Authors+Show Affiliations

Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Copenhagen, Denmark. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, |University of Copenhagen, Copenhagen, Denmark.Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Copenhagen, Denmark. Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden.Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA, USA.Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, |University of Copenhagen, Copenhagen, Denmark.Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Copenhagen, Denmark. lars.edvinsson@med.lu.se. Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. lars.edvinsson@med.lu.se.Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Copenhagen, Denmark.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31718551

Citation

Edvinsson, Jacob C A., et al. "C-fibers May Modulate Adjacent Aδ-fibers Through Axon-axon CGRP Signaling at Nodes of Ranvier in the Trigeminal System." The Journal of Headache and Pain, vol. 20, no. 1, 2019, p. 105.
Edvinsson JCA, Warfvinge K, Krause DN, et al. C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. J Headache Pain. 2019;20(1):105.
Edvinsson, J. C. A., Warfvinge, K., Krause, D. N., Blixt, F. W., Sheykhzade, M., Edvinsson, L., & Haanes, K. A. (2019). C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. The Journal of Headache and Pain, 20(1), 105. https://doi.org/10.1186/s10194-019-1055-3
Edvinsson JCA, et al. C-fibers May Modulate Adjacent Aδ-fibers Through Axon-axon CGRP Signaling at Nodes of Ranvier in the Trigeminal System. J Headache Pain. 2019 Nov 12;20(1):105. PubMed PMID: 31718551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. AU - Edvinsson,Jacob C A, AU - Warfvinge,Karin, AU - Krause,Diana N, AU - Blixt,Frank W, AU - Sheykhzade,Majid, AU - Edvinsson,Lars, AU - Haanes,Kristian A, Y1 - 2019/11/12/ PY - 2019/10/05/received PY - 2019/10/29/accepted PY - 2019/11/14/entrez PY - 2019/11/14/pubmed PY - 2020/2/26/medline KW - Aδ-fibers KW - C-fibers KW - CASPR KW - CGRP KW - Node of Ranvier, KW - Trigeminal ganglion SP - 105 EP - 105 JF - The journal of headache and pain JO - J Headache Pain VL - 20 IS - 1 N2 - 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. SN - 1129-2377 UR - https://www.unboundmedicine.com/medline/citation/31718551/C_fibers_may_modulate_adjacent_Aδ_fibers_through_axon_axon_CGRP_signaling_at_nodes_of_Ranvier_in_the_trigeminal_system_ DB - PRIME DP - Unbound Medicine ER -