Sodium Flashcards
What NaV’s are interesting for pain and why?
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
Where has most of our knowledge of NaV subtypes come from?
Genetic studies using knockout mice or antisense/siRNA knockdown experiments
When do Nav1.3 transcript levels rise in adult sensory neurons?
following axotomy and inflammation
What role might Nav1.3 play in chronic pain and what suggests this?
sustaining high frequency firing or bursts of action potentials
re-expression of NaV1.3 along with its rapid recovery from inactivation
What two methods were used to investigate Nav1.3 in pain?
antisense oligonucleotides and knockout mice
What did antisense knockdown studies of Nav1.3 show (and who?)
Hains and colleagues,2004 -> antisense knockdown of NaV1.3 expression attenuated pain-related behaviour associated with both spinal cord injury and chronic constriction injury.
Why were there conflicting results with Nav1.3 knockdown (and which researchers found this)?
Different Nav1.3 antisense constructs and knockout mice found no change in pain-related behaviour – (Lindia et al., 2005; Nassar et al.,2006)
What suggests that TTX-S channels play a role in pathogenesis of certain pain conditions?
Low dose TTX inhibits thermal and mechanical hypersensitivity in a chemotherapy-induced neuropathic pain model
What is paroxysmal extreme pain disorder?
mechanical stimulation evokes excruciating pain
What does functional characterisation of PEPD Nav1.7 mutants show and what are the implications of this?
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
What did biophysical characterisation of erythermyalgia mutants show (and who showed this)?
a significant hyperpolarising shift in voltage-dependence of activation (Cummins et al.,2007)
What are the implications of erythermyalgia mutant characteristics?
Enhancement of channel activation results in neuronal hyperexcitability that underlies the chronic inflammatory pain sensations experienced by these patients.
What did selective knockdown of Nav1.7 show (who and how was the knockdown achieved)?
Yeomans and colleagues (2005) found that selective knockdown with siRNA encoded by a viral vector attenuates inflammatory hyperalgesia.
Do Nav1.7 blockers support evidence that Nav1.7 plays a role in pain (who)?
A class of benzazepinone NaV1.7 blockers reversed tactile allodynia in a rat model of neuropathic pain (Hoyt et al.,2007).
What leads to faster re-priming of Nav1.8?
Voltage-dependence of activation and inactivation is more depolarised for NaV1.8 than 1.9
Why is it important that Nav1.8 has fast re-priming?
Contribute to continuous firing activity during sustained depolarisations
What type of studies show that Nav1.8 is important in inflammation (and who)?
Antisense
Kahsar, Gold & Levine, 1998
What do antisense oligonucleotides of Nav1.8 show (who?)?
Attenuate the development and maintenance of neuropathic pain (Joshi et al., 2006)
What does siRNA selective knockdown of Nav1.8 show (who?)
Reverses mechanical allodynia (Dong et al.,2007).
What does Nav1.8 knockout show (who)?
NaV1.8 knockout mice show normal neuropathic pain behaviour (Nassar et al.,2005).
What might explain the discrepancy between knockdown and knockout Nav1.8 studies?
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.
What suggests Nav1.9 has a role in inflammatory pain?
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.
What is the name of the Nav1.7 blocker that went through clinical trials in May,2017?
PF-05089771
What two Nav1.7 blocking compounds were discovered Moyer and colleagues (2018)?
AM-8145 and AM-0422
