Hogan Quinn H, Poroli Mark
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Brain Res. 2008 May 1;1207:102-10. doi: 10.1016/j.brainres.2008.02.066. Epub 2008 Mar 5.
In various excitable tissues, the hyperpolarization-activated, cyclic nucleotide-gated current (I(h)) contributes to burst firing by depolarizing the membrane after a period of hyperpolarization. Alternatively, conductance through open channels I(h) channels of the resting membrane may impede excitability. Since primary sensory neurons of the dorsal root ganglion show both loss of I(h) and elevated excitability after peripheral axonal injury, we examined the contribution of I(h) to excitability of these neurons. We used a sharp electrode intracellular technique to record from neurons in nondissociated ganglia to avoid potential artefacts due to tissue dissociation and cytosolic dialysis. Neurons were categorized by conduction velocity. I(h) induced by hyperpolarizing voltage steps was completely blocked by ZD7288 (approximately 10 microM), which concurrently eliminated the depolarizing sag of transmembrane potential during hyperpolarizing current injection. I(h) was most prominent in rapidly conducting Aalpha/beta neurons, in which ZD7288 produced resting membrane hyperpolarization, slowed conduction velocity, prolonged action potential (AP) duration, and elevated input resistance. The rheobase current necessary to trigger an AP was elevated and repetitive firing was inhibited by ZD7288, indicating an excitatory influence of I(h). Less I(h) was evident in more slowly conducting Adelta neurons, resulting in diminished effects of ZD7288 on AP parameters. Repetitive firing in these neurons was also inhibited by ZD7288, and the peak frequency of AP transmission during tetanic bursts was diminished by ZD7288. Slowly conducting C-type neurons showed minimal I(h), and no effect of ZD7288 on excitability was seen. After spinal nerve ligation, axotomized neurons had less I(h) compared to control neurons and showed minimal effects of ZD7288 application. We conclude that I(h) supports sensory neuron excitability, and loss of I(h) is not a factor contributing to increased neuronal excitability after peripheral axonal injury.
在各种可兴奋组织中,超极化激活的环核苷酸门控电流(I(h))通过在一段时间的超极化后使膜去极化,从而促进爆发式放电。或者,静息膜的开放I(h)通道的电导可能会妨碍兴奋性。由于背根神经节的初级感觉神经元在周围轴突损伤后显示出I(h)丧失和兴奋性升高,我们研究了I(h)对这些神经元兴奋性的作用。我们使用尖锐电极细胞内技术从未解离的神经节中的神经元进行记录,以避免由于组织解离和胞质透析导致的潜在假象。神经元按传导速度分类。超极化电压阶跃诱导的I(h)被ZD7288(约10 microM)完全阻断,同时消除了超极化电流注入期间跨膜电位的去极化凹陷。I(h)在快速传导的Aalpha/beta神经元中最为显著,在这些神经元中,ZD7288使静息膜超极化,减慢传导速度,延长动作电位(AP)持续时间,并提高输入电阻。触发AP所需的阈电流升高,ZD7288抑制重复放电,表明I(h)具有兴奋性影响。在传导较慢的Adelta神经元中,I(h)不太明显,导致ZD7288对AP参数的影响减弱。ZD7288也抑制这些神经元的重复放电,并且在强直爆发期间AP传播的峰值频率被ZD7288降低。传导缓慢的C型神经元显示出最小的I(h),并且未观察到ZD7288对兴奋性的影响。在脊神经结扎后,与对照神经元相比,轴突切断的神经元的I(h)较少,并且应用ZD7288的影响最小。我们得出结论,I(h)支持感觉神经元的兴奋性,并且I(h)的丧失不是周围轴突损伤后神经元兴奋性增加的一个因素。
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