Ion Channels

Question 1

Nav1.7 - mice

Answer 1

KO mice
- increased pressure threshold when KO in Nav1.8 neurones, all DRG and DRG + sympathetics
- decreased cold threshold (greater when KO all DRG or DRG + sympathetics)
- increased heat threshold (greatest when KO all DRG or DRG + sympathetics)

• Nav1.8 = role in inflammatory pain, less in neuropathic pain
• Nav1.9 = role in both inflammatory and neuropathic pain

Question 2

Nav1.7 - humans

Answer 2

1. familial primary erytheromelalgia
2. paroxysmal extreme pain disorder
3. congenital insensitivity to pain and anosmia
4. alterations to touch

Question 3

Nav1.7 - familial primary erythromelalgia

Answer 3

• dominant inherited neuropathy manifests as burning pain/redness of extremities
• hyperpolarising shift in Nav1.7 activation and slower inactivation

Question 4

Nav1.7 - paroxysmal extreme pain disorder

Answer 4

• inherited neuropathy
• burning rectal, ocular and mandibular pain
• mutations affect fast inactivation
• persistent currents

Question 5

Nav1.7 - congenital insensitivity to pain and anosmia

Answer 5

• nonsense mutations
• truncated, non-functional Nav1.7 subunits
• shows key role of Nav1.7 in pain
• hypofunctional Nav1.7 mutations also cause CIP via a depolarising shift in activation threshold

Question 6

Nav1.7 - alterations to touch

Answer 6

• CIP individuals find touch less pleasant
• KO Nav1.7 = decreased Nav currents and increased withdrawal threshold
• implications for systemic Nav1.7 blockade

Question 7

Nav1.7 debate

Answer 7

• Nav1.7 blockade and anti-Nav1.7 Abs only show partial efficacy
• naloxone reverses to pain phenotypes in mice
• and reverses analgesia in Nav1.7 null humans
• Nav1.7 antagonist + opioid = increased efficacy than Nav1.6 blockade alone
• no impact of naloxone in Nav1.7 KO mice
• Nav1.7 selective inhibitor = dose-dependent analgesia
• autonomic side effects are an issue
• Nav1.7 inhibitor caused dose-dependent decrease in blood pressure in monkeys
• orthostatic hypertension means Nav1.7 blockade unlikely to be a clinical target

Question 8

Nav1.8 + 1.9 - humans

Answer 8

Nav1.8
- mutations = small fibre neuropathy

Nav1.9
- mutant = CIP
- due to overactive Nav1.9
- causing nociceptor depolarising block
- other Nav1.9 mutations can cause painful neuropathy (depolarised RMP = reduced AP threshold)