(iv). Action in the nodes of Ranvier – axon-axon interaction.
The exploration of CGRP and its receptor have so far yielded successful
scientific breakthroughs and therapies. RAMP1 and CLR are co-expressed
mainly in larger neurons and in the thinly myelinated fibres, typically
identified as Aδ-fibres (Edvinsson et al., 2019; Eftekhari, Salvatore,
Calamari, Kane, Tajti & Edvinsson, 2010). CGRP receptors are found
distally in the dura mater, associated both with the vessels and at
avascular sites. In larger arteries, these fibres run in the adventitia,
close to the C-fibres. Interestingly, the C-fibres storing CGRP could
align with adjacent nodes of Ranvier in the Aδ-fibres (Edvinsson et al.,
2019). This led to the suggestion that at the nodes of Ranvier local
release of CGRP may act on CGRP receptors on the Aδ-fibres to modify the
sensory signalling. In this region, CLR/RAMP1 as well as a complete CGRP
receptor antibody immunoreactivity were observed on the Aδ-fibres and
associated with protein kinase A, which provides a link towards the
possible phosphorylation of ion channels in Aδ-fibres (Edvinsson et al.,
2019). This mechanism may alter ion channel activity at the Aδ-fibres
and contribute to the understanding of pain signalling and perhaps also
the sensitization processes. The nodes are defined by their lack of the
many layers of myelinated Schwann cells, which is why they may be a
target for therapeutic drugs such as gepants and mAbs to interact within
the trigeminal system and the pain perception.