ENDOCANNABINOID CEREBROSPINAL FLUID LEVELS IN MIGRAINE 77 4 Introduction Migraine is a highly prevalent, disabling, primary brain disorder clinically characterized by attacks of severe headache and associated symptoms.1 There are no diagnostic biomarkers and migraine is diagnosed according to clinical criteria1 Depression and anxiety are common comorbid disorders.2, 3 Although much progress has been made in unravelling the pathophysiology of attacks, little is known about why migraine attacks develop. Research into neurochemistry in people with migraine between attacks may help elucidate its etiology and provide useful biomarkers. The endocannabinoid system has a strong influence on neurotransmission, the neuroendocrine and neuroimmune systems,4-6 which are also involved in migraine pathophysiology.7, 8 Previous studies have indicated that endocannabinoids (eCBs) play a role in the trigeminovascular system, a key component in migraine pathophysiology.9, 10 The endocannabinoid system consists of two cannabinoid receptors (CB1 en CB2) and their lipid signaling ligands, the eCBs.11 CB 1 receptors are expressed throughout the peripheral and central nervous system, whereas CB2 receptors are mainly located on immune cells. 12 The two most widely studied eCBs are N-arachidonoylethanolamine, also called anandamide (AEA) and 2-arachidonoylglycerol (2-AG). AEA is a partial agonist for both cannabinoid receptors, with a high affinity for the CB1 and a low affinity for the CB2. 11 Additionally, AEA is a full agonist at the transient receptor potential vanilloid 1 (TRPV1) where it modulates the release of calcitonin gene-related peptide (CGRP). CGRP is a key neurotransmitter of the trigeminovascular system and instrumental in causing migraine attacks.13-15 2-AG is a full agonist at CB1 and CB2 receptors and probably the major synaptic eCB ligand in nervous tissue.11, 16 Endocannabinoid signaling is a key regulator of synaptic communication through retrograde inhibition of the release of inhibitory and excitatory neurotransmitters.17, 18 The CB 1 receptor particularly is strongly involved in inhibiting the release of gamma-aminobutyric acid (GABA), serotonin, glutamate, and CGRP, all believed to play an important role in migraine.6, 9, 15, 19 Several studies suggest that the endocannabinoid system modulates the trigeminovascular system in migraine.9, 20-22 In a small study, AEA was suggested to be lower in the cerebrospinal fluid (CSF) and palmitoylethanolamide (PEA) to be higher in chronic migraine.20 Fatty acid amide hydrolase (FAAH), which degrades AEA, and endocannabinoid membrane transporter (EMT) activity in platelets were increased in women with migraine but not in men, suggesting an altered endocannabinoid system that seems more profound in female patients.23 Gene expressions and peripheral protein levels of endocannabinoid system components were elevated in the blood of people with migraine.24 At the same time, evidence has emerged for a role of the endocannabinoid system in depression,25 which has a bidirectional relationship with migraine.26 Women with depression have reduced endocannabinoid levels in blood serum,27 and chronic treatment with antidepressants can alter the endocannabinoid system.28
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