Emesis and migranies (Concepts)

Question 1

What is the process of 5-HT (serotonin) synthesis?

Answer 1

Tryptophan →(Tryptophan hydroxylase)→ 5-Hydroxytryptophan →(Dopa decarboxylase)→ 5-HT

Question 2

What is the rate-limiting step in 5-HT syntheses?

Answer 2

Tryptophan → 5-Hydroxytryptophan

Question 3

What are the isoforms of tryptophan hydroxylase (Tph) and were are they expressed?

Answer 3

• Tph1 = Enterochromaffin cells
• Trp2 = Neurones

Question 4

How do platelets acquire 5-HT

Answer 4

• They cannot synthesise it themselves.
• They load 5-HT using SERT (serotonin transproter) while circulating through intestines

Question 5

How is 5-HT degraded?

Answer 5

1. Oxidative deamination by MAO
2. Oxidation to 5-HIAA by aldehyde dehydrogenase

Question 6

What are the most important 5-HT receptors?

Answer 6

1. 5-HT_1(A-F) (G_i-coupled)
2. 5-HT_2(A-C) (G_q-coupled)
3. 5-HT₃ (ionotropic, LGIC)

Question 7

Which part of the brain mediates vomiting reflex?

Answer 7

Vomiting centre (medulla)

Question 8

What are the areas controlling vomiting projecting into the vomiting centre?

Answer 8

1. Cortical centres:
   - Emotional factors
   - Repulsive sight/smell
2. Chemoreceptor trigger zone (CTZ):
   - Noxious substances in blood
   - Inputs from visceral afferents and vestibular nuclei
3. Vagal afferents (detection of noxious substances in GI tract):
   - Direct
   - Indirect (via chemoreceptor trigger zone)
4. Vestibular nuclei (via CTZ)

Question 9

What is the main NT and receptors mediating vomiting?

Answer 9

NT = 5-HT

Receptor = 5-HT₃

Question 10

What are the symptoms of migranes?

Answer 10

• Severe headache (initially unilateral)
• Nausea & vomiting
• Photophobia
• Prostration (weakness)

Question 11

What are the types of migranes?

Answer 11

• Migranes with aura: Progressive visual disturbance (aura) ~30 minutes preceding headache, followed by headache.
• Migranes without aura: Headache without visual distubances.

Question 12

What are the theories behind the causes of migranes?

Answer 12

1. Vascular hypothesis
2. Brain hypothesis
3. Inflammation hypothesis

Question 13

What is the vascular hypothesis of migranes?

Answer 13

1. Intracerebral vasodilation causes aura
2. Extracerebral vasodilation causes headache

Question 14

What is the brain hypothesis of migranes?

Answer 14

• Wave if cortical spreading depression (CSD) spreads across the brain at rate of ~2m/s and is responsibe for aura and headache.
• CSD causes inhibition of neuronal activity by depolarisation.
• Can be caused by increased [K⁺]_e as a result of neuronal hyperactivity.

Question 15

What is the inflammation hypothesis of migranes?

Answer 15

• Activation of the trigeminal nerve nociceptors in meninges and extracranial vessels causes direct generation of nociceptor signals, causing headache.
• Neurogenic inflammation is secondary to this event.

Question 16

What evidence suggests there is a strong linke between 5-HT and migrane pathogenesis?

Answer 16

1. There is significant increase in urine 5-HIAA during migrane attacks.
2. There is a decrease in blood 5-HT during migranes.
3. Drugs that target 5-HT are very effective in treating migranes.