Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy.
Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy.
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DOI：
10.1186/1471-2202-13-15
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发表时间：
2012-01-30
期刊：
影响因子：
2.4
通讯作者：
Henry JL
中科院分区：
文献类型：
--
作者：
Zhu YF;Henry JL
神经损伤后神经性疼痛的原因尚不清楚，限制了基于机制的治疗方法的发展。动物模型提供了一些方向，但对于特定的感觉神经元以诱导和维持感觉疼痛通路激活的方式发生变化的情况知之甚少。我们之前的研究表明，在袖带诱发的神经性疼痛动物模型中，Aβ（通常是非伤害性神经元）在激活脊髓伤害性神经元方面发生了变化，而本研究专门针对确定这些神经元兴奋性的任何变化。因此，本研究旨在记录 Aβ 纤维背根神经节 (DRG) 神经元的细胞内情况，并确定外周感受野、细胞体和背根的兴奋性。通过在右侧坐骨神经周围插入两个薄的聚乙烯套囊，在斯普拉格道利大鼠中诱导周围神经病变。三周后，即急性电生理学实验之前，所有动物均被证实对冯弗雷丝表现出触觉过敏。在稳定的细胞内记录条件下，神经元根据其对其周围感受野自然激活的反应进行功能分类。此外，背根的传导速度、动作电位的配置和对刺激的适应率也是分类标准。兴奋性被测量为外周感受野激活的阈值、对细胞内注射去极化电流到体细胞的反应以及对背根电刺激的反应。在对照动物中，所有神经元的机械阈值均在正常范围内。神经病大鼠中的 Aβ DRG 神经元表现出对感受野刺激的平均机械阈值显着低于对照大鼠，刺激后放电时间延长，激活阈值降低，对注入体细胞的去极化电流有更大的反应，以及对背根配对脉冲电刺激的更长的不应期和延迟反应。本研究证明了周围神经病变神经完整动物模型中功能分类的 Aβ 低阈值和高阈值 DRG 神经元的变化，该模型表现出对正常无害的皮肤刺激的伤害性反应，与在患有神经性疼痛的人类中观察到的情况非常相似。我们进一步证明，这些神经元的外周感受野更容易兴奋，体细胞也是如此。然而，背根表现出兴奋性下降。因此，如果这些神经元参与神经病理性疼痛，那么兴奋性的差异变化可能会对诱导中枢敏化的外周驱动产生影响，至少在周围神经病理性疼痛的动物模型中是如此，并且 Aβ 感觉神经元可能因此导致人类周围神经损伤后的异常性疼痛和自发性疼痛。
Causes of neuropathic pain following nerve injury remain unclear, limiting the development of mechanism-based therapeutic approaches. Animal models have provided some directions, but little is known about the specific sensory neurons that undergo changes in such a way as to induce and maintain activation of sensory pain pathways. Our previous studies implicated changes in the Aβ, normally non-nociceptive neurons in activating spinal nociceptive neurons in a cuff-induced animal model of neuropathic pain and the present study was directed specifically at determining any change in excitability of these neurons. Thus, the present study aimed at recording intracellularly from Aβ-fiber dorsal root ganglion (DRG) neurons and determining excitability of the peripheral receptive field, of the cell body and of the dorsal roots. A peripheral neuropathy was induced in Sprague Dawley rats by inserting two thin polyethylene cuffs around the right sciatic nerve. All animals were confirmed to exhibit tactile hypersensitivity to von Frey filaments three weeks later, before the acute electrophysiological experiments. Under stable intracellular recording conditions neurons were classified functionally on the basis of their response to natural activation of their peripheral receptive field. In addition, conduction velocity of the dorsal roots, configuration of the action potential and rate of adaptation to stimulation were also criteria for classification. Excitability was measured as the threshold to activation of the peripheral receptive field, the response to intracellular injection of depolarizing current into the soma and the response to electrical stimulation of the dorsal roots. In control animals mechanical thresholds of all neurons were within normal ranges. Aβ DRG neurons in neuropathic rats demonstrated a mean mechanical threshold to receptive field stimulation that were significantly lower than in control rats, a prolonged discharge following this stimulation, a decreased activation threshold and a greater response to depolarizing current injection into the soma, as well as a longer refractory interval and delayed response to paired pulse electrical stimulation of the dorsal roots. The present study has demonstrated changes in functionally classified Aβ low threshold and high threshold DRG neurons in a nerve intact animal model of peripheral neuropathy that demonstrates nociceptive responses to normally innocuous cutaneous stimuli, much the same as is observed in humans with neuropathic pain. We demonstrate further that the peripheral receptive fields of these neurons are more excitable, as are the somata. However, the dorsal roots exhibit a decrease in excitability. Thus, if these neurons participate in neuropathic pain this differential change in excitability may have implications in the peripheral drive that induces central sensitization, at least in animal models of peripheral neuropathic pain, and Aβ sensory neurons may thus contribute to allodynia and spontaneous pain following peripheral nerve injury in humans.
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