GENERAL DISCUSSION 213 10 combining both metabolomic and genomics data better insights into the metabolism and comorbidity underlying disease can be provided, which will eventually lead to the identification of new diagnostic and therapeutic targets. Such approach has already been successful in cancer research, where the integration of metabolomics data with genomics data led to the identification of new drug targets.17, 18 Interplay between biochemical systems In Chapters 4 and 5 we investigated endocannabinoids and prostaglandin E2 levels, respectively, in relation to migraine risk. Although we did not find any differences in concentrations between migraineurs and controls, these studies did show that both systems are very complex and influenced by many factors. Illustrative of the complexity of both the endocannabinoid and prostaglandin system is the role the transient receptor potential vanilloid 1 (TRPV1) cation channel has in both systems. TRPV1 is a nonselective cation channel, predominantly expressed in sensory neurons, about 40-50% of the trigeminal sensory neurons express TRPV1.19-21 It is believed that TRPV1 has a role in nociception, which makes it a molecular target for pain treatment.20, 22 The channel has a preference for calcium and can be activated by numerous stimuli, such as pH < 5.9, heat, but TRPV1 is also sensitive to endocannabinoids and prostaglandins.20, 23 Activation of TRPV1 causes calcitonin-gene related peptide (CGRP) release.24 Two of the most well-known endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) were investigated in this thesis. These endocannabinoids are synthesised on demand from lipid membrane phospholipids and have a half-life of only minutes due to rapid degradation by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively.25-27 AEA and 2-AG are partial agonist for the cannabinoid receptors (CB1 and CB2). The CB1 receptor is strongly involved in inhibiting the release of gammaaminobutyric acid (GABA), serotonin, glutamate, and CGRP, all neurotransmitters believed to play an important role in migraine.28-31 It has been shown that AEA activates the TRPV1 channel on trigeminal ganglion neurons. Thus promoting the release of calcitonin-gene related peptide (CGRP) independent of any action at the CB1. 32 Thus AEA can both inhibit and stimulate CGRP release via CB1 and TRPV1, respectively. 30, 33 In addition, there are various studies that indicate that TRPV1 is co-expressed with either CB1, CB2 or both, in neuronal and non-neuronal cells. 33 Therefore, AEA may have a distinct role in nociception, both being pronociceptive at TRPV1 and antinociceptive at cannabinoid receptors.34 Similarly, prostaglandins work in a complex manner as they act on various receptors including EP1, EP2, EP3, EP4 and IP that activate different G protein-coupled signalling pathways.35 It has been shown that the activation of EP1/ EP4 and IP by PGE2 and PGI2, respectively, is critical for TRPV1 sensitization.36 In addition, PGE 2 has been shown to increase TRPV1 expression, cell surface and axonal trafficking.37, 38 In addition, PGE 2 also has an interaction with CGRP, as it stimulates the release of CGRP in rat trigeminal neurons, trigeminal ganglia and trigeminal
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