PROSTAGLANDIN-E2 LEVELS OVER THE COURSE OF GLYCERYL TRINITRATE PROVOKED MIGRAINE ATTACKS 97 5 Introduction Migraine is a common multifactorial paroxysmal brain disorder with a life-time prevalence of 15-20%, causing disability worldwide.1, 2 A typical migraine attack consists of a preictal, an ictal (aura and/or headache), and a postictal (postdromal) phase.3 The pathophysiological mechanisms underlying migraine attacks, however, remain to be fully elucidated. Notably, migraine-like attacks can be induced in subjects with migraine, but not in healthy controls, by the administration of glyceryl trinitrate (GTN), a donor of nitric oxide (NO). Two types of NO-induced headaches have been reported (Figure 1).4 First, in both migraine subjects and healthy controls an immediate headache develops within the first hour of GTN infusion. This headache is of mild to medium severity and typically resolves within an hour after GTN administration. Second, only in subjects with migraine, a delayed onset migraine-like headache (moderate to severe, accompanied by associated symptoms such as nausea, vomiting, photo- and/or phonophobia) may develop within 12 hours after GTN infusion.5, 6 This different response to GTN in cases compared to controls may provide clues for mechanisms underlying migraine attacks. Whereas the immediate headache seems related to a direct action of the NO-cGMP pathway via vasodilation by smooth muscle relaxation,7, independent of neuropeptide calcitonin gene-related peptide (CGRP) release,8 the delayed migraine-like attack is thought to be the result of trigeminovascular activation mediated via CGRP release.5, 7, 9 Figure 1 Schematic headache pattern after the start of the GTN infusion consisting of the immediate headache and the migraine-like attack Three different response groups can be distinguished. The red two-dot chain line represents a typical headache pattern for a subject with migraine who responded to GTN (GTN responder),this is combined with typical patterns for a subject with migraine who did not respond to GTN (GTN non-responder) represented by the contineous green line, and a healthy control represented by the dotted blue line. GTN, glyceryl trinitrate. Adapted from Onderwater et al.21 Besides CGRP there is ample evidence that prostaglandins may be pivotal in the development of GTN-induced migraine-like attacks, and possibly spontaneous migraine attacks.10 NO stimulates cyclooxygenase (COX-1 and COX-2) synthesis, which are enzymes that produce prostaglandins. 11 Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin synthesis, are a first
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