Actions of Nociceptive Mediators in the Trigeminovascular System as a Basis for the Generation of Headaches

Nociceptive mechanisms in the trigeminovascular system are probably involved in the generation of different forms of hedaches, wherein the neuropeptide CGRP (calcitonin gene-related peptide), which is released from a subset of activated primary afferents, is regarded as an important mediator. CGRP is not only a potent vasodilator but is also involved in nociceptive transmission in the trigeminal nucleus. Inhibition of CGRP receptors by the high-affinity CGRP receptor antagonist BIBN4096BS, which had proved its therapeutic potency in migraine patients, led to a significant decrease in neuronal activity in the spinal trigeminal nucleus of the rat. Another important vasodilatory mediator in meningeal nociception seems to be nitric oxide (NO), which may facilitate CGRP release from peripheral and central trigeminal structures. Inhibition of NO generation was effective in lowering the neuronal activity in the spinal trigeminal nucleus as well, whereas infusion of NO donors led to an increase in activity. The activiation showed typically a biphasic pattern. The delayed response can only be explained by secondary processes such as the expression of pro-nociceptive substances in the trigeminal nucleus or ganglion, as indicated by preliminary experimental studies. The fact that clinical and basic experimental data complement each other highlights the interpretative value of basic experiments for the pathophysiological mechanisms underlying the generation of headaches.