Background
Migraine is a neurological disorder that afflicts up to 16 % of the adult population in the Western countries [1]. It is episodic, often with moderate to severe disabling headache, associated with sensory and autonomic symptoms, phonophobia and photophobia, and cognitive symptoms. Many researchers consider migraine to be a disorder in which Central Nervous System (CNS) dysfunction plays a pivotal role while various parts of the trigeminovascular system are necessary for the expression of peripheral symptoms and aspects of pain [2].
Several drugs have been shown to reduce migraine symptoms, or elicits migraine-like attacks [3]. Studies, both in man and in experimental animals, have revealed anti-migraine effects of triptans, gepants (calcitonin gene-related peptide (CGRP) antagonists) and CGRP antibodies [4–7]. However, due to the size and the pharmacokinetics of these drugs it is suggested that only a modest passage may occur across the blood-brain barrier (BBB) [8]. The published figures on BBB passage are in the vicinity of 3 % when given at clinically effective doses of triptans/gepants [5, 9–11]. While these molecules have a small size, the CGRP antibodies will not likely cross the BBB at all and therefore unlikely to antagonize receptor sites within the CNS [5].
In order to neutralize this argument some researchers have suggested that the BBB is modified during migraine attacks and may show enhanced passage [12]. From a purely mechanistic viewpoint the BBB consists of a myriad of molecules, including metalloproteases, as well as claudins and integrins which would negate a dynamic opening of the closed tight junctions which are an essential part of the BBB [13, 14]. Another aspect that must be considered, that has not been proven, is modification of transport guided passage across the BBB which could be modified during the attacks.
Therefore, it is possible that candidates for targets of migraine treatment may reside outside the BBB; the dural vasculature, the trigeminal ganglion (TG) and in CNS regions lacking a BBB such as pituitary and pineal glands [15] and at nerve afferents that connect to the TG. The dural vasculature, including the middle meningeal artery (MMA) has long been considered as a target based on the vasogenic theory of migraine [16, 17]. We and others have shown that both sumatriptan and telcagepant can inhibit CGRP induced vasodilation in the human MMA, illustrating one of its potential targets [18, 19]. However, not all vasodilators cause migraine and triptans are not effective in all migraine patients [20].
The other possibility is the activation and involvement of the TG with its afferents which innervates the dura mater and the MMA [21]. Based on preceding studies on TG cell [22] and TG organ cultures [23], we have recently shown that the addition of complete Freund’s adjuvant (CFA) or inflammatory soup (IS) on the dura mater causes an increase in phosphorylated extracellular signal-regulated kinases (p-ERK1/2) activation and interleukin (IL)-1β expression in the ipsilateral TG [24]. The application of inflammatory substances on the dura mater, in addition to chemical stimulation of the dural receptive fields, cause hypersensitivity to mechanical and thermal stimulation, as well as activation in the TG and in brain stem trigeminal neurons, similar to what could be expected in migraine [17, 24]. BBB permeability has never been investigated using this model. It is highly relevant to ask this question as it has been suggested that the BBB might change during a migraine attack in effort to explain how anti-migraine drugs can reach the CNS [12, 25–28]. In addition, it is relevant to compare the permeability to the TG and evaluate any potential alterations.
Here we report that there are no differences in the permeability into the CNS after experimental inflammation and there are no significant changes in brain water content or in permeability. Interestingly, we show that the TG is more than 30 times more permeable than the CNS at normal conditions and thereby supporting the idea that anti-migraine drugs may reach much higher and clinically relevant levels within the TG than they do in the CNS.