These findings suggest a mechanism by which the inhibition of the excitatory amino acid receptors by kynurenic acid and its derivatives can alter trigeminal nociception.

In parallel to serotonin synthesis, the major route of tryptophan catabolism is the kynurenine pathway, which produces neuroactive metabolites. Among these substances, kynurenic acid has potential neuroprotective action blocking glutamate release and glutamatergic neurotransmission. Glutamate is a key player in migraine pathogenesis; it is crucial in the communication of first and second-order neurons, and it has an important role in the genesis of cortical spreading depression, which is the electrophysiological correlate for migraine aura and may be involved in the activation of the trigeminal system. Thus, kynurenines may affect the pathogenesis directly, by acting on glutamate receptors and exerting other neuromodulatory effects, and indirectly via an altered serotonin metabolism. This work summarizes our current results regarding the role of the kynurenine system in trigeminal activation and other events occurring during migraine headache.

Migraine is one of the commonest neurological disorders. Despite intensive research, its exact pathomechanism is still not fully understood and effective therapy is not always available. One of the key molecules involved in migraine is glutamate, whose receptors are found on the first-, second- and third-order trigeminal neurones and are also present in the migraine generators, including the dorsal raphe nucleus, nucleus raphe magnus, locus coeruleus and periaqueductal grey matter. Glutamate receptors are important in cortical spreading depression, which may be the electrophysiological correlate of migraine aura. The kynurenine metabolites, endogenous tryptophan metabolites, include kynurenic acid (KYNA), which exerts a blocking effect on ionotropic glutamate and α7-nicotinic acetylcholine receptors. Thus, KYNA and its derivatives may act as modulators at various levels of the pathomechanism of migraine. They can give rise to antinociceptive effects at the periphery, in the trigeminal nucleus caudalis, and may also act on migraine generators and cortical spreading depression. The experimental data suggest that KYNA or its derivatives might offer a novel approach to migraine therapy.

Migraine is a common, paroxysmal, highly disabling primary headache disorder with a genetic background. The primary cause and the origin of migraine attacks are enigmatic. Numerous clinical and experimental results suggest that activation of the trigeminal system (TS) is crucial in its pathogenesis, but the primary cause of this activation is not fully understood. Since activation of the peripheral and central arms of the TS might be related to cortical spreading depression and to the activity of distinct brainstem nuclei (e.g. the periaqueductal grey), we conclude that migraine can be explained as an altered function of the neuronal elements of the TS, the brainstem, and the cortex, the centre of this process comprising activation of the TS. In light of our findings and the literature data, therefore, we can assume that migraine is mainly a neuronal disease.

No abstract