Sodium leak channel contributes to neuronal sensitization in neuropathic pain

•Increase of NALCN expression and function in DRG and dorsal spinal cord contributes to CCI-induced neuronal sensitization.•Knockdown of NALCN expression in DRG and spinal cord prevented CCI-induced neuronal sensitization.•Persistent knockdown or conditional knockout of NALCN completely prevented the development of CCI-induced pain behaviors.•NALCN is an underlying new target for control of neuropathic pain. Neuropathic pain affects up to 10 % of the total population and no specific target is ideal for therapeutic need. The sodium leak channel (NALCN), a non-selective cation channel, mediates the background Na+ leak conductance and controls neuronal excitability and rhythmic behaviors. Here, we show that increases of NALCN expression and function in dorsal root ganglion (DRG) and dorsal spinal cord contribute to chronic constriction injury (CCI)-induced neuropathic pain in rodents. NALCN current and neuronal excitability in acutely isolated DRG neurons and spinal cord slices of rats were increased after CCI which were decreased to normal levels by NALCN-siRNA. Accordingly, pain-related symptoms were significantly alleviated by NALCN-siRNA-mediated NALCN knockdown and completely prevented by NALCN-shRNA-mediated NALCN knockdown in rats or by conditional NALCN knockout in mice. Our results indicate that increases in NALCN expression and function contribute to CCI-induced neuronal sensitization; therefore, NALCN may be a novel molecular target for control of neuropathic pain.