NaV1.X

Nota:

•    Gene SCN1A, CNS/ heart  TTX-sensitive   Expressed- high in large-diameter neurons, moderate in medium-diameter neurons, and low in small-diameter neurons 

1. Experiments
   1. Mutations in SCN1A

      Nota:

      • have been associated with inherited epileptic syndromes and familial hemiplegic migraine in humans 
   2. preclinical studies

      Nota:

      • level of Nav1.1 mRNA was decreased in the injured DRG after peripheral spinal nerve ligation (SNL) or spared nerve injury (SNI) 
      1. ?

         Nota:

         • Thus, whether and how DRG Nav1.1 is involved in neuropathic pain development is still elusive and remains to be further studied
2. NOT a good target

   Nota:

   • >> because of its role in various function, it is not a good target for therapies for neuropathic pain   

Nota:

•    Gene- SCN2A, CNS  One of the predominate Na channels in the nervous system

1. Location

   Nota:

   • dendrites, unmyelinated axons, and premyelinated axons 
2. Experiments

   Nota:

   • Peripheral nerve injury and inflammation do not alter the levels of Nav1.2 mRNA or protein in the DRG 
3. NOT a good target

   Nota:

   •    The evidence suggests that DRG Nav1.2 is unlikely to be involved in the development of neuropathic pain.   

Nota:

• Gene SCN3A  Present in the foetal DRG, and CNS TTX-sensitive Mostly present in DRG which are medium or large in size 

1. Experiments
   1. +

      Nota:

      • the experiemtns suggest- increase in Nav1.3 in DRG and dorsal horn might be involved in nerve injury-induced pain hypersensitivities
      1. Expression

         Nota:

         • 1. L5 ventral root transection produces a TNFα-dependent increase in Nav1.3 at both the mRNA and protein levels in the L4 and L5 DRGs 
         • 2. Nav1.3 protein was also found to accumulate in neuromas of patients with painful neuropathy 
      2. Knockdown/out

         Nota:

         • Hains et al- attenuated pain hypersensitivities induced by spinal cord injury and sciatic nerve CCI
         • Samad et al., 2013- Virus-mediated shRNA Knockdown of Nav1.3 in Rat Dorsal Root Ganglion Attenuates Nerve Injury-induced Neuropathic Pain 
      3. Electrophys

         Nota:

         • Estacion et al., 2012- Using ramp stimuli >>K354Q NaV1.3 epilepsy-associated mutant channel, which is known to display an enhanced persistent current and demonstrate a strong correlation with the second component of the ramp response  >> enhanced ramp current in K354Q mutant channels can contribute in several ways to hyperexcitability and abnormal spontaneous firing that contribute to hyperexcitability disorders, such as epilepsy and neuropathic pain 
      4. NF-κB inhibitor

         Nota:

         • Zang et al., 2010- The data suggested that injury to ventral root might lead to neuropathic pain and the re-expression of Nav1.3 in primary sensory neurons by activation of NF-κB >> also while NF-kB wasn’t completely dependent on the presence of TNF-a, it blocks the up-regulation of Nav1.3 induced by rrTNF in cultured DRG neurons in a dose-dependent manner
   2. -
      1. Knockdown/out

         Nota:

         • Lindia et al. - did not attenuate SNI-induced mechanical or cold allodynia, although it did significantly block the SNI-induced increase in DRG Nav1.3
         • neuropathic pain development remained intact in both conventional and conditional Nav1.3 knockout mice 
         • ectopic discharges from the injured nerves were unaffected in the absence of Nav1.3 in conventional knockout mice 
   3. ?

      Nota:

      • Discrepancy due to differences between rats and mice >> evidence for diff in NaV1.8 between species