(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.