Upregulation of the sodium channel NaV?4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation.

ABSTRACT: High-frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all isoforms in adult DRG, NaV1.6 is the main carrier of tetrodotoxin-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons, the regulatory ?4 subunit is potentially the endogenous blocker. We used in vivo siRNA-mediated knockdown of NaV?4 to examine its role in the DRG inflammation model. NaV?4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRG showed that NaV?4 siRNA blocked the inflammation-induced increase in spontaneous activity of A? neurons and reduced repetitive firing and other measures of excitability. NaV?4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression, and this was reversed by NaV?4 siRNA, based on immunohistochemistry and Western blotting. NaV?4 siRNA also reduced immunohistochemical NaV1.6 expression. Patch-clamp recordings of tetrodotoxin-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current, effects blocked by NaV?4 siRNA. NaV?4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing NaV1.6.

SUBMITTER: Xie W 

PROVIDER: S-EPMC4939223 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature