APPENDICES 238 S analysis was corrected for sex, age, BMI, weekly alcohol consumption, cigarettes per day, and comorbid lifetime depression. No differences were found in endocannabinoid levels between migraine subgroups and when compared to controls. However, several of the possibly confounding factors (sex, smoking, age, and BMI, and comorbid lifetime depression) did have a significant effect on endocannabinoid levels. Most striking is the effect on depression on endocannabinoid levels, given that depression is a comorbid disorder of migraine. This study is illustrative for the complexity of the endocannabinoid system, where it is important to take into consideration the contribution of confounding factors. In Chapter 5 the role of prostaglandin-E2 (PGE2) in relation to a provoked migraine attack was investigated. It has been shown that intravenous infusion of PGE2 is able to provoke a migrainelike headache. Contrary to other provocation substances, such as glyceryl trinitrate (GTN), calcitonin gene-related peptide (CGRP), which show a delay of several hours in provoking a migraine attack, PGE2 causes a very rapid onset of an attack, i.e. within 1 hour.The fact that PGE2 causes such a rapid attack onset, suggests that PGE2 may be at the end of the signalling pathway towards an attack, so PGE2 might be closely upstream of GTN-induced migraine attacks. To reliable investigate the role of PGE2 over the course of an attack, blood samples from 37 women with migraine and 25 age-matched female controls were obtained at three time points, i.e. (1) before provocation with GTN and (2) ~140 min and (3) ~320 min after migraine provocation with GTN. After analysis with a generalized linear mixed-effect model, no differences were found in PGE2 levels between the interictal and preictal state nor between the interictal and ictal state. This suggests that rise in PGE2 is not essential for the initiation of GTN-induced migraine-like attacks. Part II Genetics of different headache forms The aim of Part 2 was to uncover the genetical underpinnings of multiple headache disorders. Apart from migraine we looked also at the genetic underpinnings of cluster headache and hemiplegic migraine. Cluster headache is characterized by excruciating unilateral headaches or facial pain accompanied by ipsilateral facial autonomic symptoms and/or restlessness. Hemiplegic migraine is a subtype of migraine with aura, where the aura phase is associated with motor weakness that can go into a hemiplegia. In most chapters (Chapters 6,7 and 8) of Part 2 genome-wide association studies (GWAS) were used to investigate differences in the genetic architecture between cases and controls. In GWAS several millions of single nucleotide polymorphisms (SNPs) are tested for association with a trait by assessing differences in allele frequencies between large numbers of patients and controls. In addition, in Chapter 9 we used a next-generation sequencing approach where the whole exome is sequenced and looked for differences between hemiplegic migraine patients and controls in a targeted approach by testing genes that belong to the family of voltagegated calcium channel alpha subunits.
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