Department of Neurology, University Hospital Essen, Germany.
Eur J Pain. 2013 Jul;17(6):881-92. doi: 10.1002/j.1532-2149.2012.00260.x. Epub 2012 Dec 11.
Lacosamide is a novel anti-epileptic drug that enhances the slow- and not fast-inactivating state of voltage-gated sodium channels. Lacosamide has demonstrated analgesic efficacy in several animal studies but preclinical studies on neuropathic pain models are rare, and recent clinical trials showed no superior analgesic effects.
Here, we examine whether an acute or chronic administration of lacosamide (3-60 mg/kg, i.p.) attenuates pain behaviour induced by spinal nerve ligation (SNL). To validate the inhibitory efficacy of lacosamide on voltage-gated sodium channels, sodium currents in naïve and SNL-injured dorsal root ganglion (DRG) neurons were recorded using whole-cell patch clamping.
Lacosamide only marginally attenuated thermal hyperalgesia, but not tactile allodynia when applied once 7 or 14 days after SNL and showed no analgesic effect when applied daily for 19 days. In naïve neurons, 100 μmol/L lacosamide inhibited sodium channel currents by 58% and enhanced the slow inactivation (87% for lacosamide vs. 47% for control). In contrast, lacosamide inhibited sodium currents in injured DRG neurons by only 15%, while the effects on slow inactivation were diminished. Isolated currents from the NaV 1.8 channel subtype were only marginally changed by lacosamide.
The reduced effectiveness of lacosamide on voltage-gated sodium channel currents in injured DRG neurons may contribute to the reduced analgesic effect observed for the SNL model.
拉科酰胺是一种新型抗癫痫药物，可增强电压门控钠离子通道的慢失活和非快失活状态。拉科酰胺在几项动物研究中表现出镇痛疗效，但在神经病理性疼痛模型中的临床前研究很少，最近的临床试验也没有显示出优越的镇痛效果。
在这里，我们研究了急性或慢性给予拉科酰胺（3-60mg/kg，腹腔注射）是否可以减轻脊神经结扎（SNL）引起的疼痛行为。为了验证拉科酰胺对电压门控钠离子通道的抑制作用，我们使用全细胞膜片钳技术记录了在体和 SNL 损伤背根神经节（DRG）神经元中的钠离子电流。
拉科酰胺仅轻度减轻热痛觉过敏，但在 SNL 后 7 或 14 天单次给药时，对触觉性痛觉过敏没有作用，并且在连续 19 天给药时也没有镇痛作用。在正常神经元中，100μmol/L 拉科酰胺抑制钠离子电流 58%，增强慢失活（拉科酰胺为 87%，对照为 47%）。相比之下，拉科酰胺仅抑制损伤的 DRG 神经元中的钠离子电流 15%，而对慢失活的影响则减弱。从 NaV 1.8 通道亚型分离的电流仅被拉科酰胺轻度改变。
拉科酰胺在损伤的 DRG 神经元中对电压门控钠离子通道电流的作用降低，可能导致 SNL 模型中观察到的镇痛效果降低。
