Sodium

Question 1

What NaV’s are interesting for pain and why?

Answer 1

4 particularly interesting subtypes due to their distribution in nociceptors -> tetrodotoxin-sensitive (TTX-S) channels Nav1.3 + Nav1.7 + tetrodotoxin-resistant (TTX-R) channels NaV1.8 and NaV1.9

Expression + properties of these channels alter in animal models of pain -> may contribute to altering pain thresholds

Question 2

Where has most of our knowledge of NaV subtypes come from?

Answer 2

Genetic studies using knockout mice or antisense/siRNA knockdown experiments

Question 3

When do Nav1.3 transcript levels rise in adult sensory neurons?

Answer 3

following axotomy and inflammation

Question 4

What role might Nav1.3 play in chronic pain and what suggests this?

Answer 4

sustaining high frequency firing or bursts of action potentials

re-expression of NaV1.3 along with its rapid recovery from inactivation

Question 5

What two methods were used to investigate Nav1.3 in pain?

Answer 5

antisense oligonucleotides and knockout mice

Question 6

What did antisense knockdown studies of Nav1.3 show (and who?)

Answer 6

Hains and colleagues,2004 -> antisense knockdown of NaV1.3 expression attenuated pain-related behaviour associated with both spinal cord injury and chronic constriction injury.

Question 7

Why were there conflicting results with Nav1.3 knockdown (and which researchers found this)?

Answer 7

Different Nav1.3 antisense constructs and knockout mice found no change in pain-related behaviour – (Lindia et al., 2005; Nassar et al.,2006)

Question 8

What suggests that TTX-S channels play a role in pathogenesis of certain pain conditions?

Answer 8

Low dose TTX inhibits thermal and mechanical hypersensitivity in a chemotherapy-induced neuropathic pain model

Question 9

What is paroxysmal extreme pain disorder?

Answer 9

mechanical stimulation evokes excruciating pain

Question 10

What does functional characterisation of PEPD Nav1.7 mutants show and what are the implications of this?

Answer 10

attenuation of fast inactivation of NaV1.7 resulting in persistent sodium currents.

Deficit in inactivation may promote a prolonged action potential and repetitive firing in response to a stimulus

Question 11

What did biophysical characterisation of erythermyalgia mutants show (and who showed this)?

Answer 11

a significant hyperpolarising shift in voltage-dependence of activation (Cummins et al.,2007)

Question 12

What are the implications of erythermyalgia mutant characteristics?

Answer 12

Enhancement of channel activation results in neuronal hyperexcitability that underlies the chronic inflammatory pain sensations experienced by these patients.

Question 13

What did selective knockdown of Nav1.7 show (who and how was the knockdown achieved)?

Answer 13

Yeomans and colleagues (2005) found that selective knockdown with siRNA encoded by a viral vector attenuates inflammatory hyperalgesia.

Question 14

Do Nav1.7 blockers support evidence that Nav1.7 plays a role in pain (who)?

Answer 14

A class of benzazepinone NaV1.7 blockers reversed tactile allodynia in a rat model of neuropathic pain (Hoyt et al.,2007).

Question 15

What leads to faster re-priming of Nav1.8?

Answer 15

Voltage-dependence of activation and inactivation is more depolarised for NaV1.8 than 1.9

Question 16

Why is it important that Nav1.8 has fast re-priming?

Answer 16

Contribute to continuous firing activity during sustained depolarisations

Question 17

What type of studies show that Nav1.8 is important in inflammation (and who)?

Answer 17

Antisense

Kahsar, Gold & Levine, 1998

Question 18

What do antisense oligonucleotides of Nav1.8 show (who?)?

Answer 18

Attenuate the development and maintenance of neuropathic pain (Joshi et al., 2006)

Question 19

What does siRNA selective knockdown of Nav1.8 show (who?)

Answer 19

Reverses mechanical allodynia (Dong et al.,2007).

Question 20

What does Nav1.8 knockout show (who)?

Answer 20

NaV1.8 knockout mice show normal neuropathic pain behaviour (Nassar et al.,2005).

Question 21

What might explain the discrepancy between knockdown and knockout Nav1.8 studies?

Answer 21

Given that selective blockers of NaV1.8 inhibit neuropathic pain (Jarvis et al.,2007), it is possible that genetic compensatory mechanisms mask some role in neuropathic pain for NaV1.8 in the knockout mouse.

Question 22

What suggests Nav1.9 has a role in inflammatory pain?

Answer 22

NaV1.9 knockout mice have greatly reduced, or absent inflammatory hyperalgesia induced by formalin, carrageenan, complete Freund’s adjuvant and prostanoids (Priest et al.,2005) or in response to inflammatory mediators such as bradykinin, serotonin and ATP (Amaya et al.2006).

Activation of PKC pathways potentiates NaV1.9-like currents in sensory neurons.

Question 23

What is the name of the Nav1.7 blocker that went through clinical trials in May,2017?

Answer 23

PF-05089771

Question 24

What two Nav1.7 blocking compounds were discovered Moyer and colleagues (2018)?

Answer 24

AM-8145 and AM-0422

Question 25

What was an early Nav1.8 blocker?

Answer 25

A-803467

Question 26

What did use of an early Nav1.8 blocker show?

Answer 26

abolished evoked action potential firing and suppressed spontaneous firing in isolated sensory neurons.

efficacy in behavioural assays of acute mechanical pain, inflammatory thermal hyperalgesia and neuropathic pain (Jarvis et al.,2007) but couldn’t be used in man.