Part 3 - Neuro-vascular hypothesis
The descending paths of pain
The descending pain pathways (figure 3) make it possible to modulate the nociceptive response, either by facilitating it, which ultimately contributes to a chronicization of the pain, or by inhibiting it. The origin of this modulation can occur at the segmental and supra-segmental level. Several human neuroimaging studies have demonstrated in migraine an alteration in the activity of suprasegmental structures involved in this modulation, such as the PAG, the RVM, the LC or the hypothalamus. (Afridi et al. 2005; Maniyar et al. 2014; Moulton et al. 2014)
A. The PAG-RVM complex
The PAG and the RVM were the first key structures identified in supra-segmental modulation. These two structures are closely connected. The PAG receives projections from the Sp5C which then projects onto the RVM. The latter in turn sends projections to the Sp5C. (Osipov et al. 2010). RVM modulates nociception bidirectionally and can facilitate or inhibit pain. This capacity for two-way control comes from two classes of neurons called "ON cells" and "OFF cells", and neutral cells, particularly serotonergic ones. OFF cells have been reported to exert an inhibitory effect on nociceptive transmission, while ON cells have a pronociceptive action (Chen et al. 2019).
In rats, the application of an inflammatory soup to the dura mater leads to an increase in the activity of the ON cells of the RVM (Edelmayer et al. 2009). It has also been proven the involvement of OFF cells in the mechanisms of inhibitory pain controls at the level of the NRM (Chebbi et al. 2014). Studies on PAG have shown that injections of opioids or electrical stimulation applied to PAG cause a powerful anti-nociceptive effect in animals (Reynolds 1969; Tsou et al. 1964) as well as in humans (Hosobuchi, et al 1977, Richardson et al 1977). It is now well established that the PAG is a fundamental area in the inhibition of pain by opiates (Ossipov et al. 2010).
In addition, an imaging study showed PAG activation during a placebo effect (Eippert et al. 2009). Similarly, this activation also leads to concomitant activity of the RVM neurons and is associated in rats with a decrease in defensive reflexes (Behbehani et al. 1979). Through their afferent and efferent projections to the LC or the amygdala, PAG and RVM are able to modulate pain, but also sleep-wake cycles, hunger or muscle tone. Thus, there could be a link between the triggering factors of migraine such as hunger or lack of sleep with these structures or with the autonomic signs felt by patients during an attack (fatigue, loss of tone, disgust by food ).
B. The locus coeruleus
The locus coeruleus is a primarily noradrenergic and cholinergic structure that participates in the sleep-wake cycle. The potential role of LC in the pathophysiology of migraine is supported by both preclinical and clinical evidence. It is sensitive to trigemino-vascular activation (Tassorelli et al. 1995; Ter Horst et al. 2001). It is involved in the modulation of many excitatory circuits, plays a role in pain, cognition, stress, and nociception (Schwarz and Luo 2015).
The LC can modulate the neurons of the trigeminal nucleus (Sasa et al. 1973) and its stimulation leads to α2-adrenergic receptor-dependent cerebral hypoperfusion (Goadsby et al. 1989). Stimulation of these receptors is indeed a known trigger of cortical pervasive depression (CPD), the presumed underlying phenomenon of migraine aura (Takano et al. 2007). During wakefulness, the LC receives descending excitatory projections from the hypothalamus that promote its activation (Voisin et al. 2005).
In turn, the LC sends upward noradrenergic projections to the CNS, thalamus, and cortex, as well as downward projections to the CST and spinal cord (Goadsby et al. 2017). As the LC has an essentially diurnal activity and is practically absent during sleep, it is possible that its nocturnal inhibition is at the origin of the alleviation of the pain felt during a migraine attack. Conversely, it may explain why sleep cycle disturbances are a very common factor in patients.
C. The hypothalamus
The hypothalamus also has numerous anatomical connections with pain modulation zones and the trigeminal nucleus (Bartsch et al. 2005; May et al. 2019; Abdallah et al. 2013). A study showed by MRI an activation of the hypothalamus during a migraine attack, as well as a persistent increase in blood flow after the attack and after the administration of sumatriptan (Denuelle et al. 2007).
Orexinergic neurons are present in number in the hypothalamus; they are involved in wakefulness, appetite, pain and some autonomic functions (Holland et al. 2007). This orexinergic system is increasingly studied in the pathophysiology of migraine. Pharmacological blockade of orexin receptors inhibits DCE in rats and also attenuates meningeal arterial vasodilation caused by nociceptive activation of the trigeminal system (Hoffmann et al. 2015). The dopaminergic system also seems to be involved. Indeed, the premonitory symptoms found during migraine attacks such as fatigue, yawning, changes in appetite and nausea involve the activation of the dopaminergic system (Akerman et al. 2007).
Application of dopamine or agonist within the CST inhibits their activation after nociceptive stimulation. The dopaminergic A11 nucleus of the hypothalamus could be the probable source of this dopamine.
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