GENERAL INTRODUCTION 11 1 treatment in patients and lead to novel drug targets, and ultimately novel drugs. This has already been shown for several diseases other than migraine or cluster headache, for instance cardiac troponin helps diagnose myocardial infarction and different biomarkers have been developed for the diagnosis of ovarian cancer.39-41 A way to investigate whether endogenous signalling molecules are involved in migraine pathology is by trying to provoke an attack in “a human model”. When an attack can be provoked with a certain trigger, this suggests the involvement of a related mechanism underlying the disease. Several chemical molecules have been implicated in migraine, identified as they can trigger attacks. The triggers are mostly vasoactive substances that are present at or near the nerve fibres. It has been shown that glyceryl trinitrate (GTN), an nitric oxide (NO) donor, is able to induce an immediate headache in almost all subjects and a delayed migraine-like attack in close to 70% of migraineurs but not in controls.42, 43 Other substances, such as calcitonin gene-related peptide (CGRP), PACAP and prostaglandin E2 (PGE2) and I2 (PGI2) are also able to trigger migraine-like attacks.44-47 Although attacks of cluster headache have been successfully triggered with GTN and histamine, it is not common practice to investigate cluster headache using provocation studies.48 In addition to investigating trigger mechanisms per se, provocation studies can also be used to study other aspects of migraine, such as consequences of attacks, as investigating spontaneous attacks is notoriously difficult as they occur unexpectedly. In contrast, in provocation studies, the set-up can be meticulously controlled. Another way of investigating relevant substances in disease is by measuring compounds in body fluids, such as cerebrospinal fluid (CSF), blood and urine, and compare profiles in disease vs. control samples. The compounds, being proteins (proteomics) or metabolites (metabolomics), are representative of aspects of the phenotype at the molecular level. For instance, altered blood plasma levels of serotonin (5-HT) in migraine patients were found in the late eighties.49 This finding contributed to the development of triptans, i.e. 5-HT-1D/1F receptor agonists, which are used for aborting migraine attacks. Serotonin is an amine, just like other neurotransmitters implicated in migraine pathophysiology, such as glutamate and gamma-aminobutyric acid (GABA). This led to amines to be further investigated in the pathogenesis of migraine.50 Recently, a lot of biochemical research was done on CGRP, which is believed to play an important role in migraine and cluster headache. As mentioned earlier, infusion of CGRP is able to induce migraine-like attacks in migraine patients.47 In addition, studies show an increase in CGRP levels in blood between cases and controls outside51-57 or during a migraine attack,53, 57-61 although almost as many studies have not found a difference in CGRP levels in blood outside58, 60, 62-65 or during59, 65 migraine attacks. Regardless, newly approved monoclonal antibodies (mAbs) that target CGRP or its receptor have a beneficial effect on the headache frequency in patients with migraine.66, 67 In cluster headache, CGRP also seems to be involved68, 69 with CGRP plasma levels being higher for cluster headache patients during an active period compared to those outside, after provocation with sublingual GTN.70 In cluster headache, randomized controlled trials on CGRP antibodies in patients have been initiated but with unconvincing results sofar.71 However, the reliability of measuring CGRP is not without controversy.65, 72
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