Elevated Expression and Activity of Sodium Leak Channel Contributes to Neuronal Sensitization of Inflammatory Pain in Rats.

Jia Li,Peilin Lu,Jin Liu,Donghang Zhang,Yali Chen,Yunxia Zuo,Peng Liang,Jiefei Shen,Cheng Zhou,Changhong Miao

doi:10.3389/fnmol.2021.723395

Abstract

Inflammatory pain encompasses many clinical symptoms, and there is no satisfactory therapeutic target. Neuronal hyperexcitability and/or sensitization of the primary nociceptive neurons in the dorsal root ganglion (DRG) and spinal dorsal horn are critical to the development and maintenance of inflammatory pain. The sodium leak channel (NALCN), a non-selective cation channel, mediates the background Na+ leak conductance and controls neuronal excitability. It is unknown whether abnormal activity of NALCN mediates the pathological process of inflammatory pain. Complete Freund’s adjuvant (CFA) was injected into the left footpad of rats to induce inflammatory pain. The thresholds of mechanical and thermal sensation and spontaneous pain behaviors were assessed. The expression of NALCN in DRG and spinal dorsal cord was measured. NALCN currents and the contribution of NALCN to neuronal excitability in the DRG and spinal dorsal cord were recorded using whole-cell patch-clamping recording. NALCN was abundantly expressed in neurons of the DRG and spinal dorsal cord. In acutely isolated DRG neurons and spinal cord slices from rats with CFA-induced inflammatory pain, NALCN currents and neuronal excitability were increased. Subsequently, intrathecal and sciatic nerve injection of NALCN-small interfering RNA (siRNA) decreased NALCN mRNA and reverted NALCN currents to normal levels, and then reduced CFA-induced neuronal excitability and alleviated pain symptoms. Furthermore, pain-related symptoms were significantly prevented by the NALCN-shRNA-mediated NALCN knockdown in DRG and spinal cord. Therefore, increased expression and activity of NALCN contributed to neuronal sensitization in CFA-induced inflammatory pain. NALCN may be a novel molecular target for the control of inflammatory pain.

Highlights

Inflammatory pain is induced by neural injury or disease that affects approximately 20% of the general population; a large proportion of patients with inflammatory pain is treated ineffectively (Goldberg and McGee, 2011)
The present study suggests that increased expression and function of sodium leak channel (NALCN) in the dorsal root ganglion (DRG) and spinal dorsal horn were associated with the behavioral hyperalgesia induced by inflammatory pain
Our findings indicate that NALCN regulates the excitability of sensory neurons and may cause inflammatory pain

Summary

Introduction

Inflammatory pain is induced by neural injury or disease that affects approximately 20% of the general population; a large proportion of patients with inflammatory pain is treated ineffectively (Goldberg and McGee, 2011). Several causes may contribute to the development of inflammatory pain. Current therapeutics for inflammatory pain mainly include non-steroidal anti-inflammatory drugs and opioids, but the effects are not satisfactory and their use are limited because of side effects (Weinblatt, 1991; Mehta, 2007; Carter et al, 2014). The development of novel drugs is clinically important for the treatment of inflammatory pain. Neuronal hyperexcitability and/or sensitization of the primary nociceptive neurons in the dorsal root ganglion (DRG) and spinal dorsal horn is critical to the development and maintenance of inflammatory pain (Herrmann et al, 2017; Amsalem et al, 2018). The key molecular target that regulates the intrinsic excitability of neurons in DRG and spinal dorsal horn during the development of inflammatory pain has yet to be identified

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