ArticleThe journal of headache and pain2019
C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system.
Article in The journal of headache and pain, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 113 citations in OpenAlex.
- A 2-Part, Open-Label, Phase 1 Bioequivalence and Food-Effect Study of Ubrogepant in Healthy Adult Participants.Clinical pharmacology in drug development · 2025Trial
- Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab.The journal of headache and pain · 2022Trial
- Trial
- A delayed endothelial-glial mechanism for CGRP-induced migraine.The journal of headache and pain · 2026Review
- Nociceptive action of calcitonin gene-related peptide in the trigeminovascular system.Nature reviews. Neurology · 2026Article
- A Fluorescence Imaging-Based 3D Analysis Pipeline for Mouse Trigeminal Ganglion Neurons.Biosensors · 2026Article
- CGRP-targeted migraine treatment and early pathophysiology in experimental subarachnoid hemorrhage.The journal of headache and pain · 2026Article
- Non-neuronal targets for migraine therapy.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Bridging the gap: molecular mechanisms, regional activity and connectivity in headache disorders.Brain : a journal of neurology · 2026Review
- TRPM3 activation causes CGRP release in trigeminal neurons: Implications for migraine mechanisms.Headache · 2026Article
- Hypothalamic and sex-related hormones in migraine.The journal of headache and pain · 2026Review
- Expression of melatonin receptors in trigeminal and sphenopalatine ganglia: potential targets for primary headache disorders.The journal of headache and pain · 2025Article
- Hallmarks of primary headache: part 3 - cluster headache.The journal of headache and pain · 2025Review
- Late response to anti-CGRP therapy for migraine.Pain management · 2025Review
- Immunohistochemical Analysis of Maxillary Nerve Distribution in Rats.Anesthesia progress · 2025Article
- PACAP versus CGRP in migraine: From mouse models to clinical translation.Cephalalgia : an international journal of headache · 2025Review
- The Role of Inflammation in Migraine Headaches: A Review.FASEB bioAdvances · 2025Review
- Ex vivo stimulation of the trigeminal nucleus caudalis induces peripheral CGRP release in the trigeminal ganglion and reveals a distinct dopamine-endocannabinoid mechanism relevant to migraine.The journal of headache and pain · 2025Article
- Exploring the role of ubiquitination modifications in migraine headaches.Frontiers in immunology · 2025Review
- Sex differences in expression of CGRP family of receptors and ligands in the rat trigeminal system.The journal of headache and pain · 2024Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 6 institutions in 3 countries.
Funding
Abstract
backgroundMonoclonal 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).
methodsWith 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.
resultsAntibodies 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.
conclusionWe 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.