Pain 2

Question 1

Which four voltage-gated sodium channels are found in the adult CNS?

Answer 1

Na1.1, Na1.2, Na1.6, and Na1.7

Question 2

Which two voltage-gated sodium channels are found in the dorsal root ganglia, and are hence involved in pain?

Answer 2

Na1.8 and Na1.9

Question 3

Which sodium channel is found in the foetal brain?

Answer 3

Na1.3

Question 4

What is the overall charge of a voltage-gated sodium channel?

Answer 4

-1, counteracting the +1 of the sodium ion

Question 5

Which voltage-gated sodium channels are immune to tetrodotoxin (TTX)?

Answer 5

Na1.5, Na1.8, and Na1.9

Question 6

Which mutation increases Na1.8 sensitivity to TTX 21,000x?

Answer 6

Serine to phenylalanine

Question 7

How are the phasic responses of Na1.8 and Na1.9 different to other voltage-gated sodium channels?

Answer 7

Na1.8 generates a phasic response very slowly, and Na1.9 does not have a phasic response at all - it just leaks sodium ions

Question 8

At what voltage does Na1.9 activate?

Answer 8

-70mV

Question 9

Which sodium channel sets the threshold for action potential generation?

Answer 9

Na1.7

Question 10

Where is Na1.7 located in dorsal root ganglia neurons?

Answer 10

The growth cone

Question 11

Describe the changes in responsiveness to thermal and mechanical stimuli in Na1.9 and Na1.7 K/O mice

Answer 11

Na1.9: No change

Na1.7: Reduced responsiveness to mechanical stimuli, normal response to thermal stimuli

Question 12

Name two conditions associated with the brain channels Na1.1 and Na1.2

Answer 12

Severe childhood epilepsy (e.g. intractable childhood tonic-clonic epilepsy and severe myoclonic epilepsy in infancy) and familial hemiplegic migraine

Question 13

State the consequences of loss of function and gain of function mutations in Na1.7

Answer 13

Loss of function: complete inability to sense pain

Gain of function: paroxysmal extreme pain disorder, an autosomal dominant disorder of pain and autonomic dysfunction

Question 14

What causes Na1.8 to lower the pain threshold?

Answer 14

Tissue damage leads to the release of PGE2, which causes PKA to phosphorylate Na1.8, leading to lowering of the threshold

Question 15

How are Na1.8 K/O mice different in their responses to painful stimuli?

Answer 15

They have diminished mechanosensation and delayed responses to inflammatory pain

Question 16

Which protein controls the translocation of Na1.8 to the plasma membrane?

Answer 16

p11

Question 17

How does p11 K/O in mice affect their response to painful stimuli?

Answer 17

It reduces the response to mechanical and thermal stimuli, due to a reduction in the sodium current

Question 18

Describe the method of action of NSAIDs

Answer 18

They prevent prostaglandin synthesis by inhibiting cyclo-oxygenase (COX)

Question 19

How does paracetamol affect COX?

Answer 19

It reversibly non-competitively inhibits it by scavenging hydroperoxidases, which usually stimulate COX

Question 20

What predisposes long-term aspirin users to gastric ulcers?

Answer 20

Aspirin irreversibly inactivates COX by acetylating it. COX-1 is vital for protecting the stomach through mucus production

Question 21

Why are there no COX-2 specific inhibitors available?

Answer 21

They appeared to increase the risk of myocardial infarction

Question 22

Name two drugs used to treat neuropathic pain

Answer 22

Gabapentin and pregabalin

Question 23

What is the theorised method of action of gabapentin and pregabalin?

Answer 23

They are believed to reduce calcium currents by binding to the alpha2delta subunit of voltage-gated calcium channels, preventing the translocation of alpha1 subunits to the plasma membrane