Mediatorwirkungen im trigeminovaskulären System als Grundlage für die nozizeptiven Vorgänge bei der Kopfschmerzentstehung

Zusammenfassung

Nozizeptive Mechanismen im trigeminovaskulären System der Hirnhäute sind vermutlich an der Entstehung von Kopfschmerzen unterschiedlichster Ursachen beteiligt. Dabei wird dem Neuropeptid CGRP (Calcitonin gene-related peptide), das von einem Teil der aktivierten primären Afferenzen des N. trigeminus freigesetzt wird, eine entscheidende Rolle zugeschrieben. CGRP wirkt nicht nur stark vasodilatorisch, sondern ist auch an der synaptischen Übertragung im Trigeminuskern beteiligt. Die Hemmung der CGRP-Rezeptoren durch den hochaffinen CGRP-Rezeptor-Antagonisten BIBN4096BS, der sich in klinischen Studien als therapeutisch bei Migräne erwiesen hatte, führte zu einer signifikanten Abnahme der neuronalen Aktivität im spinalen Trigeminuskern der Ratte. Ein weiterer wichtiger endogener vasodilatorischer Mediator der meningealen Nozizeption bzw. der Kopfschmerzentstehung scheint Stickstoffmonoxid (NO) zu sein, welches peripher und zentral im trigeminalen System die Freisetzung von CGRP fördern kann. Auch die Hemmung der endogenen NO-Produktion verminderte die neuronale Aktivität im spinalen Trigeminuskern, während die Infusion von NO-Donatoren die neuronale Aktivität steigerte. Wie in den entsprechenden klinischen Experimenten an Patienten mit primären Kopfschmerzen war die Aktivierung typischerweise biphasisch. Die verzögerte Antwort ist dabei nur durch sekundäre Prozesse wie z. B. eine Expression pronozizeptiver Substanzen im Trigeminuskern oder im Ganglion trigeminale zu erklären, worauf erste tierexperimentelle Befunde hinweisen. Die Übereinstimmung der klinisch-experimentellen Befunde mit den tierexperimentellen Daten macht deren Aussagekraft bezüglich der pathophysiologischen Mechanismen bei der Kopfschmerzentstehung deutlich.

Abstract

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.

Schlüsselwörter

Kopfschmerz - CGRP - Stickstoffmonoxid - trigeminovaskuläres System - BIBN4096BS

Key words

headache - CGRP - nitric oxide - trigeminovascular system - BIBN4096BS

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