CHAPTER 10 214 10 nucleus caudalis.39-41 Cyclooxygenases (COX-1 and COX-2) are responsible for the conversion of arachidonic acid to prostaglandins and thromboxane and the conversion of AEA and 2-AG into prostanoid-like derivatives.42 Together this shows that biological systems do not stand alone and that both AEA and PGE2 are intertwined and can converge on one pathway via the TRPV1 channel and CGRP. Given this mutual convergence, it is a perhaps not surprising that in neither study (Chapter 4 nor Chapter 5) we found a difference between migraineurs and cases. It was already known that the TRPV1 channel is an important contributor to migraine pathology.34 Furthermore, it has been demonstrated that there is an increased expression of TRPV1 in chronic migraine patients.43 Additional argumentation for the involvement of TRPV1 in migraine, are the expression of TRPV1 on the meningeal nociceptors and that their activation is known to promote the release of CGRP from sensory nerve endings.44 A future step in research would be looking more holistically to our biological system. Many components of these systems have already been investigated with the aim to develop targeted therapies. Currently migraine treatment consists of acute and preventive migraine medications that do not result in the desired effect for all patients. The efficacy (the achievement of freedom from pain or from the most bothersome symptom within 2 hours) of acute medications in clinical trials lies around 19-31%.45 The efficacy (a 50% reduction in monthly migraine days) of preventive medications lies around 40-50%.46, 47 Capsaicin, the pungent ingredient in chili peppers, is a TRPV1 agonist and has been observed to provide pain relief when used in the appropriate amount and frequency. Research has shown that repeated intranasal capsaicin treatment can reduce migraine attacks by 50-80% in chronic migraine sufferers.48 This is believed to be due to the desensitising effect of capsaicin via TRPV1, which leads to a decrease in CGRP release. SB-705498 is a chemical that acts as a competitive antagonist of the TRPV1 receptor, was found to be less effective than placebo in treating migraine headache, photophobia, and phonophobia in a phase II clinical trial.49 While several TRPV1 antagonists have been studied in clinical trials, they have failed to advance to Phase III trials due to adverse side effects such as hyperthermia or loss of thermal pain sensitivity.50 CGRP is one of the latest avenues in migraine treatment, it is known that the release of CGRP can be blocked by sumatriptan a conventional anti-migraine drug.51 Sumatriptan binds to the 5-HT-1D/1F receptor in the brain and causes constriction of the extracerebral blood vessels within the cranial vasculature, to inhibit release of inflammatory mediators. Monoclonal antibodies that target the CGRP receptor, known as gepants, have been recently approved for migraine treatment.52 Examples are, erenumab, fremanezumab en galcanezumab. Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin synthesis by inhibiting COX enzymes, are a first line treatment for migraine headaches Investigating treatment response via the PGE2 pathway was in migraine was done with the EP4 receptor antagonist BGC20-1531 in a randomised, double blind, placebo-controlled, three-way intra-individual crossover study. This studies showed that BGC20-1531 was not effective against PGE2 induced
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