(iii). Action on neuron cell bodies and nociceptive fibres.
The trigeminal system provides the link between the peripheral primary afferents and the central terminals of the trigeminal nucleus caudalis (TNC). Activation of this pathway may result in sensitization within second-order neurons and drive the CNS aspects of the migraine attacks (May & Burstein, 2019). Secondly, it has been demonstrated that activation of hypothalamus is early (prodromal) site where the migraine attack starts (May & Burstein, 2019; Schulte, Mehnert & May, 2020; Schulte, Menz, Haaker & May, 2020). Connectivity studies have revealed that other CNS regions are subsequently activated including the brainstem from with links are available to activate or modulate the trigeminal system function (May & Burstein, 2019). In both hypothesis the trigeminal system plays a key role and currently available mAbs towards CGRP and the CGRP receptor are effective (Edvinsson, Haanes, Warfvinge & Krause, 2018) despite their inability to penetrate the blood-brain barrier (Lundblad, Haanes, Grande & Edvinsson, 2015; Noseda et al., 2020).
Each of the peptides of the CGRP family exhibits a distinct selection of biological actions (Poyner et al., 2002). CGRP and AMY are the most closely related peptides in terms of amino acid sequence, which may cause an overlap in their ability to activate their receptors. CGRP and AMY are reported to have effects related to pain, though there are still limited data and it is unclear how much overlap there is because the peptides are usually not studied simultaneously. The relative potency of CGRP, CT, AMY and AM at the different receptor complexes is complicated and challenging because of cross-reactivity (Hay, Garelja, Poyner & Walker, 2018; Hendrikse, Bower, Hay & Walker, 2018). In addition, release of a peptide will result in a very high concentration just at the receptor site, while circulating levels vary considerably. The study of the nodes of Ranvier in the trigeminal system demonstrated CGRP containing boutons with CGRP containing vesicles in C-fibres that may directly release CGRP to reach the adjacent Aδ-fibres with CGRP receptors (Edvinsson et al., 2019).
The possibility of intercellular cross-talk in the TG was recently proposed to result in a feedback loop sensitizing neurons (Messlinger, Balcziak & Russo, 2020). Apart from direct gap-junction communication between SGC´s and neurons, paracrine signalling may also occur. CGRP locally released by neurons or C-fibres could potentially activate receptors located on SGC´s, other neurons or auto receptors. This activation may in turn affect gene expression, neurotropic factors, neuropeptides or receptor regulations.
There exists few direct functional studies on the various cells in the TG. Hypothetically, a range of plausible targets, available to circulating drugs with low BBB permeability, can be noted: (i) Peripheral terminals of nociceptive Aδ-fibers and C-fibres innervating various cranial structures, (ii) Receptors expressed at or proximal to the nodes of Ranvier on Aδ-fibers (Edvinsson et al., 2019), (iii) Neuron cell bodies (notably, in the TG these are vigorously enveloped by SGCs which may act as a gate-keeper to systemically introduced drugs) and (iv) the SGCs and Schwann cells in the TG (likely a complex signalling relationship between these cells and proximal neurons/axons (Messlinger, Balcziak & Russo, 2020).
A recent study demonstrated that the CGRP receptor antagonist Erenumab was internalized by both the CGRP receptor and AMY1 receptor in cultured TG neurons (Bhakta, Vuong, Taura, Wilson, Stratton & Mackenzie, 2021). Thus, there is a possibility of paracrine CGRP signalling occurring with SGC´s expressing either the CGRP receptor or the AMY1 receptor. Both receptor activation pathways lead to an upregulation of cAMP which in turn could further sensitize neurons and axons to noxious stimuli.
Non-myelinating Schwann cells form Remak bundles around parts of C-fibre axons. They are vital in providing trophic factors and regenerating damaged C-fibres (Murinson & Griffin, 2004). Disruption of non-myelinating Schwann cell ErbB signalling in mice resulted in a progressive sensory loss. This suggests intercellular signalling between non-myelinating Schwann cells and unmyelinated sensory fibres and is critical for C-fibre and Schwann cell survival. The implications of SGC and Schwann cell interactions with neurons is a field of research not yet fully understood. In part due to difficulties in studying the structures in vitro without disrupting the neuron-glia architecture.