Omana-Zapata I, Khabbaz M A, Hunter J C, Bley K R
Department of Analgesia, Roche Bioscience, Palo Alto, CA 94304, USA.
Brain Res. 1997 Oct 17;771(2):228-37. doi: 10.1016/s0006-8993(97)00770-1.
In animal models of neuropathic pain, transection or constrictive injury to peripheral nerves produces ectopic discharges originating at both injury sites and related dorsal root ganglia (DRG). In addition, hyperexcitability is observed in associated dorsal horn (DH) neurons of the spinal cord. As ectopic discharges are inhibited by agents that block voltage-sensitive Na+ channels, it has been postulated that accumulation of Na+ channels in the membrane at nerve injury sites may contribute to the development of ectopic nerve activity (ENA). The goal of the present study was to compare the sensitivity of ENA to lidocaine and QX-314, a positively charged lidocaine derivative, which is frequently assumed to be membrane impermeant. Experiments were performed on adult male Sprague-Dawley rats in which the common sciatic nerve had been transected 4-10 days earlier. Extracellular microelectrode recordings were made from DRG and DH neurons, and neuronal activity was measured in fine bundles of microfilaments teased from sciatic nerves in anesthetized and paralyzed rats. Comparative effects on heart rate (HR) and mean blood pressure (MBP) were also studied. To confirm that externally applied QX-314 is able to inhibit high frequency activity in sensory nerves, QX-314 was superfused over isolated rat vagus nerves during stimulation of compound action potentials in C-fibers (C-spikes). As expected, intravenously administered lidocaine inhibited ENA at all three sites. Lidocaine ED50 values (expressed as mg/kg, with 95% confidence limits) were: 10.2 (7.8-13.3), 1.4 (0.8-2.4) and 0.9 (0.4-2.0) for neuromas, DRG and DH neurons, respectively. QX-314 also induced dose-dependent inhibition of ENA at neuromas and DRG, but produced only a small inhibition of DH neuron ENA. QX-314 had the following ED50 values (mg/kg) for neuromas, DRG and DH neurons, respectively: 2.3 (2.0-2.8), 6.9 (4.7-26.5) and 85.7. QX-314-mediated inhibition of DRG ENA had a slow onset and was long-lasting, relative to lidocaine. Lidocaine or QX-314 also significantly reduced HR and MBP in the same dose range as that which reduced ENA in DRG or neuromas. In isolated rat vagus nerve recordings, QX-314 induced marked use-dependent inhibition of C-spike amplitude, with IC50 values (microM) of 9000 (4600-18,000) and 350 (290-420) for low- (0.03 Hz) and high-frequency (30 Hz) C-spikes, respectively. These data support the hypothesis that Na+ channel accumulation contributes to the generation of ectopic discharges in neuromas and DRG, and suggests that intravenous QX-314 can acutely block Na+ channels at these sites.
在神经性疼痛的动物模型中，对周围神经进行横断或缩窄性损伤会在损伤部位和相关的背根神经节（DRG）产生异位放电。此外，在脊髓相关的背角（DH）神经元中观察到兴奋性过高。由于异位放电可被阻断电压敏感性Na⁺通道的药物所抑制，因此推测神经损伤部位膜上Na⁺通道的积聚可能促成异位神经活动（ENA）的发生。本研究的目的是比较ENA对利多卡因和QX - 314（一种带正电荷的利多卡因衍生物，通常被认为不能透过细胞膜）的敏感性。实验在成年雄性Sprague - Dawley大鼠身上进行，这些大鼠的坐骨神经在4 - 10天前已被横断。用细胞外微电极记录DRG和DH神经元的活动，并在麻醉和麻痹的大鼠中从坐骨神经分离出的微丝细束中测量神经元活动。还研究了对心率（HR）和平均血压（MBP）的比较效应。为了证实外用的QX - 314能够抑制感觉神经中的高频活动，在刺激C纤维复合动作电位（C波峰）期间，将QX - 314灌注到离体大鼠迷走神经上。正如预期的那样，静脉注射利多卡因在所有三个部位均抑制ENA。利多卡因的半数有效剂量（ED50）值（以mg/kg表示，95%置信区间）分别为：神经瘤为10.2（7.8 - 13.3），DRG为1.4（0.8 - 2.4），DH神经元为0.9（0.4 - 2.0）。QX - 314在神经瘤和DRG处也诱导了剂量依赖性的ENA抑制，但对DH神经元ENA仅产生轻微抑制。QX - 314对神经瘤、DRG和DH神经元的ED50值（mg/kg）分别为：2.3（2.0 - 2.8）、6.9（4.7 - 26.5）和85.7。相对于利多卡因，QX - 314介导的对DRG ENA的抑制起效缓慢且持续时间长。在相同剂量范围内，利多卡因或QX - 314在降低DRG或神经瘤中ENA的同时，也显著降低了HR和MBP。在离体大鼠迷走神经记录中，QX - 314诱导了对C波峰幅度的明显使用依赖性抑制，低频率（0.03 Hz）和高频率（30 Hz）C波峰的半数抑制浓度（IC50）值（μM）分别为9000（4600 - 18,000）和350（290 - 420）。这些数据支持了Na⁺通道积聚促成神经瘤和DRG中异位放电产生的假说，并表明静脉注射QX - 314可在这些部位急性阻断Na⁺通道。
