Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada.
Anesthesiology. 2011 Oct;115(4):822-35. doi: 10.1097/ALN.0b013e31822ddf08.
The mechanisms that underlie the supraspinal central nervous system effects of systemic lidocaine are poorly understood and not solely explained by Na(+) channel blockade. Among other potential targets is the hyperpolarization-activated cation current, I(h), which is blocked by lidocaine in peripheral neurons. I(h) is highly expressed in the thalamus, a brain area previously implicated in lidocaine's systemic effects. The authors tested the hypothesis that lidocaine blocks I(h) in rat thalamocortical neurons.
The authors conducted whole cell voltage- and current-clamp recordings in ventrobasal thalamocortical neurons in rat brain slices in vitro. Drugs were bath-applied. Data were analyzed with Student t tests and ANOVA as appropriate; α = 0.05.
Lidocaine voltage-independently blocked I(h), with high efficacy and a half-maximal inhibitory concentration (IC(50)) of 72 μM. Lidocaine did not affect I(h) activation kinetics but delayed deactivation. The I(h) inhibition was accompanied by an increase in input resistance and membrane hyperpolarization (maximum, 8 mV). Lidocaine increased the latency of rebound low-threshold Ca(2+) spike bursts and reduced the number of action potentials in bursts. At depolarized potentials associated with the relay firing mode (>-60 mV), lidocaine at 600 μM concurrently inhibited a K(+) conductance, resulting in depolarization (7-10 mV) and an increase in excitability mediated by Na(+)-independent, high-threshold spikes.
Lidocaine concentration-dependently inhibited I(h) in thalamocortical neurons in vitro, with high efficacy and a potency similar to Na(+) channel blockade. This effect would reduce the neurons' ability to produce intrinsic burst firing and δ rhythms and thereby contribute to the alterations in oscillatory cerebral activity produced by systemic lidocaine in vivo.
全身应用利多卡因产生的脊髓以上中枢神经系统效应的机制尚不清楚，不能完全用钠离子通道阻滞来解释。其他潜在的靶点包括超极化激活阳离子电流 I(h)，它在外周神经元中被利多卡因阻断。I(h)在丘脑中有高度表达，丘脑是先前涉及利多卡因全身作用的脑区。作者检验了利多卡因是否能阻断大鼠丘脑皮质神经元中的 I(h)的假说。
作者在体外大鼠脑片的腹侧基底丘脑皮质神经元中进行全细胞电压和电流钳记录。药物经浴槽给药。数据采用学生 t 检验和方差分析进行分析；α=0.05。
利多卡因电压独立地阻断 I(h)，具有高效能和半抑制浓度 (IC(50))为 72 μM。利多卡因不影响 I(h)的激活动力学，但延迟失活。I(h)抑制伴随着输入电阻增加和膜超极化（最大 8 mV）。利多卡因增加了反弹低阈值 Ca(2+)爆发的潜伏期，并减少了爆发中的动作电位数量。在与中继放电模式相关的去极化电位（>-60 mV）下，600 μM 的利多卡因同时抑制了一种 K(+)电导，导致去极化（7-10 mV）和由 Na(+)非依赖性、高阈值尖峰介导的兴奋性增加。
利多卡因浓度依赖性地抑制了体外丘脑皮质神经元中的 I(h)，具有高效能和与钠离子通道阻滞相似的效力。这种效应会降低神经元产生内在爆发放电和 δ 节律的能力，从而有助于全身应用利多卡因在体内引起的脑振荡活动的改变。
