Preventive Treatment Of Migra... Health Article

Mechanism Of Action Of Preventive Medications

The migraine aura is probably due to spreading depression (SD), a wave of electrical activity (excitation followed by depression) that moves across the cerebral cortex at a rate of 2–3 mm/min. It is characterized by shifts in cortical steady-state potential, transient increases in K ⁺ , nitric oxide and glutamate, and transient increases followed by sustained decreases in cerebral blood flow [6,7] (Figure 1 ).

Headache probably results from the activation of meningeal and blood vessel nociceptors, combined with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. Trigeminal sensory neurons contain substance P (SP), calcitonin-gene-related peptide and neurokinin A. In animal models, stimulation results in the release of SP and calcitonin-gene-related peptide from sensory C-fiber terminals, and neurogenic inflammation (NI) [7]. However, the role of SP in the pathophysiology of human migraine is unclear [8].

In animal experiments, neuropeptides interact with the blood vessel wall, producing dilatation, plasma protein extravasation and platelet activation [9]. Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization), which then respond to previously innocuous stimuli such as blood vessel pulsations, causing, in part, the pain of migraine. Central sensitization of trigeminal nucleus caudalis (TNC) neurons can also occur and might have a key role in maintaining the headache [10]. Brainstem activation also occurs in migraine without aura, in part because of increased endogenous antinociceptive system activity. The migraine aura can trigger headache; SD activates trigeminovascular afferents. What initiates the activation of trigeminovascular afferents in the absence of a clinical aura? Potential mechanisms include SD in silent areas of the cerebral cortex or cerebellum. In addition, trigeminal afferents might be activated by events initiated in the brainstem. Stress can also activate meningeal plasma cells via a parasympathetic mechanism, leading to nociceptor activation [11].

Most migraine preventive drugs were designed to treat other disorders. 5-HT antagonists were developed based on the concept that migraine is due to excess 5-HT. Antidepressants downregulate 5-HT 2 and β-adrenoceptors. Anticonvulsant medications decrease glutamate levels and enhance GABA. The potential mechanisms of migraine preventive medications include:

• (i) raising the threshold to migraine activation by stabilizing a more reactive nervous system;
• (ii) enhancing antinociception;
• (iii) inhibiting SD ;
• (iv) inhibiting peripheral and/or central sensitization;
• (v) blocking neurogenic inflammation;
• (vi) modulating sympathetic, parasympathetic or 5-HT tone.

Oshinsky and Luo found that descending control from the upper brainstem, through 5-HT-mediated and norepinephrine-mediated systems, modulates the TNC and prevents central sensitization [12]. Ayata et al . have recently shown that preventive medications given chronically, but not acutely, block SD [13].

New targets are being evaluated. Gap junctions are intercellular channels that enable the diffusion of small molecules (up to 1 kDa). Vertebrate gap junction channels comprise 12 protein subunits called connexins. Gap junctions have a central role in mechanisms underlying the initiation and propagation of SD. Gap junction inhibitors abolish both astrocytic Ca ²⁺ waves in culture and SD [14].

The gap junction inhibitor tonabersat {(-)- cis -6-acetyl-4S-3-chloro-4-fluoro-benzoylamino-3,4-dihydro-2,2-dimethyl-2H-benzo[ p ]pyran-3S-ol} has entered clinical trials for migraine. Tonabersat inhibits cortical spreading depression (CSD), CSD-induced nitrous oxide release and cerebral vasodilatation. It does not constrict isolated human blood vessels but it does inhibit trigeminally induced craniovascular effects [15].