(ii). Relation to the blood-brain barrier.
In light of a vascular mechanisms of anti-migraine drugs, the possible relation of CGRP or its antagonists and the effect on dilation of cerebral arteries, must be considered. Importantly, the endothelium in these vessels restricts passage of molecules from the vessel lumen to the smooth muscle layers of the vascular wall containing CGRP nerve endings. The hypothesis was tested in isolated rat middle cerebral arteries that were cannulated and luminally perfused, enabling application of drugs to either the endothelium exposed in the lumen or the smooth muscle layers on the abluminal side of the artery (Edvinsson, Nilsson & Jansen-Olesen, 2007). In these experiments, CGRP as well as AM, AMY and CT were relaxing the artery only when applied to the abluminal surface of the cerebral artery (Edvinsson, Nilsson & Jansen-Olesen, 2007). Moreover, neither CGRP receptor antagonists (olcegepant and telcagepant) nor anti-CGRP antibodies blocked CGRP-mediated dilation when applied to the lumen; they were effective only when applied to the abluminal side. On this basis, circulating CGRP receptor antagonists and mAbs against CGRP and the CGRP receptor, all of which are effective in migraine, do not seem to be able to cross the endothelial barrier to access targets in the brain vasculature.
A neurogenic inflammation occurring in the dura has also been proposed as trigger of migraine attacks (Pietrobon & Moskowitz, 2013). However, numerous drugs that block the plasma protein extravasation component of neurogenic inflammation in the dura of animals have been tested in clinical trials but have not exhibited anti-migraine efficacy. Moreover, CGRP does not induce neurogenic inflammation in humans or rodents but mediates only the vasodilatory aspect of inflammation (Levy, Burstein & Strassman, 2005; Schain, Melo-Carrillo, Stratton, Strassman & Burstein, 2019). Although the idea of neurogenic inflammation has been discussed at length over the years the role in migraine is still not clear (Edvinsson, Haanes & Warfvinge, 2019). Aspects for and against this hypothesis are still being discussed (Hadjikhani et al., 2020; Khan et al., 2019).
Considering the BBB, the question remains “where do the gepants and mAbs act” to relieve migraine headache. Looking at the dura mater, the cerebral circulation, the brain and the TG after administration of tracers like Evans Blue or radioactive compounds to calculate the permeability surface (PS product) passage showed that the dura and the TG were freely accessible (Eftekhari, Salvatore, Johansson, Chen, Zeng & Edvinsson, 2015; Lundblad, Haanes, Grande & Edvinsson, 2015). Induction of neurogenic inflammation using the Freud’s Adjuvant or the “inflammation soup” revealed activation within the TG but no quantitative increase in PS product into the CNS. Subsequent measurements revealed minor passage by gepants (2%) or none of the mAbs (< 0, 01%) (Johnson, Morin, Wroblewski & Johnson, 2019). This is in support of a more recent study by Noseda showing that labelled fremanezumab was distributed to cranial sensory and autonomic ganglia and to the dura mater but not to the CNS in rats with uncompromised blood-brain barrier (Noseda et al., 2020). Since the TG and its peripheral ramifications (TGV system) are without the protection of the blood-brain barrier it is likely that the antimigraine site of action of the CGRP group of anti-migraine drugs reside here. This is also the reason why there is few CNS related side-effects.