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.

中文翻译：

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钠泄漏通道的表达和活性升高有助于大鼠炎症性疼痛的神经元敏化。

炎性疼痛包含多种临床症状，目前尚无满意的治疗靶点。背根神经节 (DRG) 和脊髓背角中主要伤害感受神经元的神经元过度兴奋和/或敏化对于炎性疼痛的发展和维持至关重要。钠泄漏通道 (NALCN) 是一种非选择性阳离子通道，可调节背景 Na+ 泄漏电导并控制神经元兴奋性。NALCN的异常活性是否介导炎性疼痛的病理过程尚不清楚。将完全弗氏佐剂（CFA）注射到大鼠的左足垫中以诱导炎症性疼痛。评估了机械和热感觉以及自发性疼痛行为的阈值。测量了 NALCN 在 DRG 和脊髓背索中的表达。使用全细胞膜片钳记录记录 NALCN 电流和 NALCN 对 DRG 和脊髓背索中神经元兴奋性的贡献。NALCN 在 DRG 和脊髓背索的神经元中大量表达。在 CFA 诱导的炎症性疼痛大鼠的急性分离的 DRG 神经元和脊髓切片中，NALCN 电流和神经元兴奋性增加。随后，鞘内和坐骨神经注射 NALCN 小干扰 RNA (siRNA) 降低 NALCN mRNA 并将 NALCN 电流恢复到正常水平，然后降低 CFA 诱导的神经元兴奋性并缓解疼痛症状。此外，NALCN-shRNA 介导的 DRG 和脊髓中的 NALCN 敲低显着防止了与疼痛相关的症状。所以，NALCN 表达和活性的增加有助于 CFA 诱导的炎症性疼痛中的神经元敏化。NALCN 可能是控制炎症性疼痛的新分子靶点。