Role of decreased sensory neuron membrane calcium currents in the genesis of neuropathic pain.
Role of decreased sensory neuron membrane calcium currents in the genesis of neuropathic pain.
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作者：
Q. Hogan
神经性疼痛的发病机制尚不完全清楚，治疗往往不充分。细胞质 Ca(2+) 调节神经元中的许多细胞过程。因此，本综述探讨了周围神经损伤后感觉神经元中通过电压门控 Ca(2+) 通道改变的内向 Ca(2+) 通量 (I(Ca)) 的致病作用。我们回顾了通过细胞内和膜片钳技术记录膜电流以及使用荧光指示剂记录细胞内 Ca(2+) 水平的研究，并对啮齿动物神经损伤模型进行了行为分析。部分结扎神经损伤后，在剧烈机械刺激后爪子持续抬起、摇晃和舔舐的反应是神经性疼痛的可靠指标。从具有这种行为的动物中分离出的初级感觉神经元显示，高压激活的 I(Ca) 减少了大约三分之一。低电压激活的 I(Ca) 几乎因周围神经损伤而消除。 I(Ca) 的损失导致 Ca(2+) 激活的 K(+) 电流的激活减少，这在受创伤的神经元中也直接减少。由于膜电流的这些变化，膜电压记录显示动作电位持续时间增加和后超极化减少。静息膜电位去极化和动作电位启动电流阈值降低表明兴奋性升高。轴索切除术后持续去极化过程中，受伤的伤害性神经元会出现重复放电增加。同时，细胞质 Ca(2+) 瞬变减少。总之，轴突神经元，尤其是传导疼痛的神经元，在外周损伤后会出现不稳定和兴奋性升高。在背根神经节损伤水平治疗神经元 I(Ca) 损失可能提供一种新的治疗途径。
The pathogenesis of neuropathic pain is incompletely understood and treatments are often inadequate. Cytoplasmic Ca(2+) regulates numerous cellular processes in neurons. This review therefore examines the pathogenic contribution of altered inward Ca(2+) flux (I(Ca)) through voltage-gated Ca(2+) channels in sensory neurons after peripheral nerve injury. We reviewed studies that recorded membrane currents through intracellular and patch-clamp techniques, as well as intracellular Ca(2+) levels using fluorimetric indicators, and performed behavioral analysis of rodent nerve injury models. Following nerve injury by partial ligation, a response characterized by sustained lifting, shaking, and licking of the paw after sharp mechanical stimulation is a reliable indicator or neuropathic pain. Primary sensory neurons isolated from animals with this behavior show a decrease in high-voltage activated I(Ca) by approximately one third. Low voltage-activated I(Ca) is nearly eliminated by peripheral nerve injury. Loss of I(Ca) leads to decreased activation of Ca(2+)-activated K(+) currents, which are also directly reduced in traumatized neurons. As a result of these changes in membrane currents, membrane voltage recordings show increased action potential duration and diminished afterhyperpolarization. Excitability is elevated, as indicated by resting membrane potential depolarization and a decreased current threshold for action potential initiation. Traumatized nociceptive neurons develop increased repetitive firing during sustained depolarization after axotomy. Concurrently, cytoplasmic Ca(2+) transients are diminished. In conclusions, axotomized neurons, especially pain-conducting ones, develop instability and elevated excitability after peripheral injury. Treatment of neuronal I(Ca) loss at the level of injury of the dorsal root ganglion may provide a novel therapeutic pathway.