(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.