Questions and Answers
Which 5-HT receptor subtypes are identified as responsible for migraine?
5-HT1, 5-HT2, and 5-HT3.
What effect does a fluctuation in estrogen have on serotonin, and how does this relate to migraine?
A fluctuation in estrogen decreases serotonin by affecting its metabolism, which can bring on migraine.
How do 5-HT receptors differ in their roles in migraine, and what are the effects of 5-HT on 5-HT1 and 5-HT2 subtypes?
5-HT receptors may have different roles in migraine. 5-HT on 5-HT1 subtypes may prevent migraine, while the opposite outcome is seen in 5-HT2 subtypes.
What is the mechanism of action of methysergide in providing migraine prophylaxis?
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What is the primary advantage of triptans over ergot derivatives in migraine management?
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How do ditans, such as lasmiditan, differ from triptans in their mechanism of action and side effects?
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What is the primary mechanism of action of CGRP receptor antagonists, such as Rimegepant and ubrogepant, in antimigraine therapy?
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What is the mechanism of action of monoclonal antibodies targeting CGRP or its receptors in migraine management?
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How do lysergic acid diethylamide (LSD) and methysergide interact with 5-HT receptors?
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What is the primary advantage of ditans, such as lasmiditan, over triptans in terms of side effects?
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Study Notes
5-HT Synthesis and Function
- 5-HT synthesis involves the rate-limiting enzyme tryptophan hydroxylase and is mainly degraded by the action of monoamine oxidases.
- 5-HT is best known as a neurotransmitter in the brain, but about 95% of it is synthesized, stored, and released by enterochromaffin cells in the intestinal mucosa.
5-HT and Immune System
- 5-HT signaling may modulate 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.
- In monocytes/macrophages, serotonin modulates cytokine secretion.
- Serotonin can suppress the release of TNF-α and IL-1β by activating serotonin receptors (5-HT2A).
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.
- Reduction of brain serotonin by reducing availability of its precursor tryptophan has been shown to be beneficial in the treatment of anorexia during cancer.
5-HT and Nausea/Vomiting
- Receptors of the CTZ that have been identified to induce emesis include opioid µ, κ, D2, NK-1, and 5-HT3.
- Ondansetron and Granisetron are selective serotonin antagonists used for treating chemotherapy-induced nausea and vomiting.
5-HT and Gastrointestinal Tract
- The 5-HT receptors occur on other neurons in the ENS, where they can be stimulatory (5-HT3 and 5-HT4).
- Prucalopride is a specific 5-HT4R agonist that facilitates cholinergic neurotransmission and is used in chronic idiopathic constipation.
- Cisapride is a 5-HT4 agonist that stimulates adenylyl cyclase activity in neurons, but was withdrawn due to potential serious and occasionally fatal cardiac arrhythmias.
Migraine
- Migraine is a complex neurovascular disorder marked by vasodilation of intracranial and extracerebral vessels.
- CGRP is released via activation of the trigeminovascular system.
- There are markedly decreased levels of 5-HT in migraineurs.
- Serotonin principally acts on serotonin receptors in the trigeminovascular system to lower levels of key molecules such as CGRP.
Treatment of Migraine
- Out of the 7 receptor types, 5-HT1, 5-HT2, and 5-HT3 are identified to be responsible for migraine.
- Lysergic acid diethylamide (LSD), methysergide, and other ergot derivatives bind to multiple 5-HT receptors and have antimigraine action.
- Triptans (e.g., Sumatriptan, Zolmitriptan, Rizatriptan, Frovatriptan) are potent cranial vasoconstrictors with neural antimigraine activity.
- Ditans (e.g., Lasmiditan) are serotonin receptor agonists that bind to 5-HT1F receptor subtype and have fewer side effects than triptans.
- CGRP receptor antagonists (e.g., Rimegepant, Ubrogepant) and monoclonal antibodies targeting CGRP or its receptors (e.g., Eptinezumab, Galcanezumab, Erenumab) are used as antimigraine therapy.
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Description
This quiz covers the synthesis and degradation of 5-HT, its role as a neurotransmitter, and its modulation of the peripheral immune system. It also touches on the importance of enterochromaffin cells in the intestinal mucosa.