Knockdown of sodium channel NaV1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia

Pain. 2013 Aug;154(8):1170-80. doi: 10.1016/j.pain.2013.02.027. Epub 2013 Mar 7.


Inflammatory processes in the sensory ganglia contribute to many forms of chronic pain. We previously showed that local inflammation of the lumbar sensory ganglia rapidly leads to prolonged mechanical pain behaviors and high levels of spontaneous bursting activity in myelinated cells. Abnormal spontaneous activity of sensory neurons occurs early in many preclinical pain models and initiates many other pathological changes, but its molecular basis is not well understood. The sodium channel isoform NaV1.6 can underlie repetitive firing and excitatory persistent and resurgent currents. We used in vivo knockdown of this channel via local injection of siRNA to examine its role in chronic pain after local inflammation of the rat lumbar sensory ganglia. In normal dorsal root ganglion (DRG), quantitative polymerase chain reaction showed that cells capable of firing repetitively had significantly higher relative expression of NaV1.6. In inflamed DRG, spontaneously active bursting cells expressed high levels of NaV1.6 immunoreactivity. In vivo knockdown of NaV1.6 locally in the lumbar DRG at the time of DRG inflammation completely blocked development of pain behaviors and abnormal spontaneous activity, while having only minor effects on unmyelinated C cells. Current research on isoform-specific sodium channel blockers for chronic pain is largely focused on NaV1.8 because it is present primarily in unmyelinated C fiber nociceptors, or on NaV1.7 because lack of this channel causes congenital indifference to pain. However, the results suggest that NaV1.6 may be a useful therapeutic target for chronic pain and that some pain conditions may be mediated primarily by myelinated A fiber sensory neurons.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Female
  • Functional Laterality / drug effects
  • Functional Laterality / genetics
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / pathology*
  • Hyperalgesia / chemically induced
  • Hyperalgesia / pathology*
  • Lysine / analogs & derivatives
  • Lysine / metabolism
  • Male
  • NAV1.6 Voltage-Gated Sodium Channel / deficiency*
  • NAV1.6 Voltage-Gated Sodium Channel / genetics
  • Pain Measurement
  • Pain Threshold / drug effects
  • Pain Threshold / physiology*
  • Physical Stimulation / adverse effects
  • Psychophysics
  • RNA, Small Interfering / adverse effects
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / physiology*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • NAV1.6 Voltage-Gated Sodium Channel
  • RNA, Small Interfering
  • Scn8a protein, rat
  • biocytin
  • Lysine