Pain 2 Flashcards
Which four voltage-gated sodium channels are found in the adult CNS?
Na1.1, Na1.2, Na1.6, and Na1.7
Which two voltage-gated sodium channels are found in the dorsal root ganglia, and are hence involved in pain?
Na1.8 and Na1.9
Which sodium channel is found in the foetal brain?
Na1.3
What is the overall charge of a voltage-gated sodium channel?
-1, counteracting the +1 of the sodium ion
Which voltage-gated sodium channels are immune to tetrodotoxin (TTX)?
Na1.5, Na1.8, and Na1.9
Which mutation increases Na1.8 sensitivity to TTX 21,000x?
Serine to phenylalanine
How are the phasic responses of Na1.8 and Na1.9 different to other voltage-gated sodium channels?
Na1.8 generates a phasic response very slowly, and Na1.9 does not have a phasic response at all - it just leaks sodium ions
At what voltage does Na1.9 activate?
-70mV
Which sodium channel sets the threshold for action potential generation?
Na1.7
Where is Na1.7 located in dorsal root ganglia neurons?
The growth cone
Describe the changes in responsiveness to thermal and mechanical stimuli in Na1.9 and Na1.7 K/O mice
Na1.9: No change
Na1.7: Reduced responsiveness to mechanical stimuli, normal response to thermal stimuli
Name two conditions associated with the brain channels Na1.1 and Na1.2
Severe childhood epilepsy (e.g. intractable childhood tonic-clonic epilepsy and severe myoclonic epilepsy in infancy) and familial hemiplegic migraine
State the consequences of loss of function and gain of function mutations in Na1.7
Loss of function: complete inability to sense pain
Gain of function: paroxysmal extreme pain disorder, an autosomal dominant disorder of pain and autonomic dysfunction
What causes Na1.8 to lower the pain threshold?
Tissue damage leads to the release of PGE2, which causes PKA to phosphorylate Na1.8, leading to lowering of the threshold
How are Na1.8 K/O mice different in their responses to painful stimuli?
They have diminished mechanosensation and delayed responses to inflammatory pain
Which protein controls the translocation of Na1.8 to the plasma membrane?
p11
How does p11 K/O in mice affect their response to painful stimuli?
It reduces the response to mechanical and thermal stimuli, due to a reduction in the sodium current
Describe the method of action of NSAIDs
They prevent prostaglandin synthesis by inhibiting cyclo-oxygenase (COX)
How does paracetamol affect COX?
It reversibly non-competitively inhibits it by scavenging hydroperoxidases, which usually stimulate COX
What predisposes long-term aspirin users to gastric ulcers?
Aspirin irreversibly inactivates COX by acetylating it. COX-1 is vital for protecting the stomach through mucus production
Why are there no COX-2 specific inhibitors available?
They appeared to increase the risk of myocardial infarction
Name two drugs used to treat neuropathic pain
Gabapentin and pregabalin
What is the theorised method of action of gabapentin and pregabalin?
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
