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Questions and Answers
What is the primary mechanism by which CGRP is released in migraineurs?
What is the primary effect of decreased serotonin levels in the trigeminovascular system?
What is the role of 5-HT receptors in the trigeminovascular system?
What is the effect of a drop in estrogen levels on serotonin metabolism?
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What type of molecules are used in migraine management?
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What is the current status of olcegepant and telcagepant in migraine therapy?
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What is the mechanism of action of methysergide in migraine prophylaxis?
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What is the primary difference between triptans and ergot derivatives?
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What is the primary advantage of olcegepant and telcagepant over triptans?
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What is the primary mechanism of action of sumatriptan, zolmitriptan, rizatriptan, and frovatriptan?
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Study Notes
5-HT Synthesis and Regulation
- 5-HT synthesis involves the rate-limiting enzyme tryptophan hydroxylase and is mainly degraded by monoamine oxidases.
- 95% of 5-HT is synthesized, stored, and released by enterochromaffin cells in the intestinal mucosa.
5-HT and the Immune System
- 5-HT signaling modulates the peripheral immune system.
- Different immune cells, including T cells, macrophages, mast cells, dendritic cells, and platelets, can generate, store, respond to, and/or transport serotonin.
- Serotonin modulates cytokine secretion in monocytes/macrophages and can suppress the release of TNF-α and IL-1β by activating serotonin receptors (5-HT2A).
- Neutrophil recruitment and T-cell activation can be mediated by serotonin.
5-HT and Food Intake
- Serotonin can affect food intake via activation of the anorexigenic melanocortin system involving 5-HT2c receptors.
- It also inhibits the orexigenic NPYergic system.
- Reducing brain serotonin by reducing the availability of its precursor tryptophan has been shown to be beneficial in treating anorexia during cancer.
5-HT Receptors and Functions
- 5-HT receptors occur on other neurons in the ENS, where they can be stimulatory (5-HT3 and 5-HT4).
- The availability of serotonergic prokinetic drugs has been restricted due to serious adverse cardiac events.
- Prucalopride is a specific 5-HT4R agonist that facilitates cholinergic neurotransmission.
Migraine and 5-HT Receptors
- Recurrent unilateral headache which may be accompanied by GI and visual disorders, more prevalent in females than males (3:1).
- 5-HT receptors, particularly 5-HT1, 5-HT2, and 5-HT3, are responsible for migraine.
- Serotonin principally acts on serotonin receptors in the trigeminovascular system to lower levels of key molecules such as CGRP.
Migraine Management
- Molecules that act as agonist/antagonist of 5-HT receptors in the trigeminovascular system are used in migraine management.
- CGRP receptor antagonists, such as olcegepant and telcagepant, are under consideration as antimigraine therapy.
Ergot Derivatives and Triptans
- Lysergic acid diethylamide (LSD), methysergide, and triptans (e.g., sumatriptan, zolmitriptan, rizatriptan, frovatriptan) are used in migraine treatment.
- Triptans are potent cranial vasoconstrictors with neural antimigraine activity, selectively agonist on 5-HT1B/1D receptors.
- Olcegepant and telcagepant selectively block CGRP receptors without the vasoconstrictive effect of triptans.
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