Neurogenic inflammation in the context of migraine

Despite considerable research into the pathogenesis of idiopathic headaches , such as migraine, the pathophysiological mechanisms underlying them remai n poorly understood. Although it is well established that the trigeminal ne rve becomes activated during migraine, the consequences of this activation remain controversial. One theory, based on preclinical observations, is tha t activation of trigeminal sensory fibers leads to a painful neurogenic inf lammation within the meningeal (dural) vasculature mediated by neuropeptide release from trigeminal sensory fibres and characterized by plasma protein extravasation, vasodilation, and mast cell degranulation. Effective antimi graine agents such as ergots, triptans, opioids, and valproate inhibit prec linical neurogenic dural extravasation, suggesting that this activity may b e a predictor of potential clinical efficacy of novel agents. However, seve ral clinical trials with other agents that inhibit this process preclinical ly have failed to show efficacy in the acute treatment of migraine in man. Alternatively, it has been proposed that painful neurogenic vasodilation of meningeal blood vessels could be a key component of the inflammatory proce ss during migraine headache. This view is supported by the observation that jugular plasma levels of the potent vasodilator, calcitonin gene-related p eptide (CGRP) are elevated during the headache and normalized by successful sumatriptan treatment. Preclinically, activation of trigeminal sensory fib ers evokes a CORP-mediated neurogenic dural vasodilation, which is blocked by dihydroergotamine, triptans, and opioids but unaffected by NK1 receptor antagonists that failed in clinical trials. These observations suggest that CGRP release with associated neurogenic dural vasodilation may be importan t in the generation of migraine pain, a theory that would ultimately be tes ted by the clinical testing of a CGRP receptor antagonist. (C) 2001 Wiley-L iss, Inc.