Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons
Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons
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DOI：
10.1523/jneurosci.4866-06.2007
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发表时间：
2007-03-21
影响因子：
5.3
通讯作者：
Todorovic, Slobodan M.
中科院分区：
文献类型：
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作者：
Jagodic, Miljen M.;Pathirathna, Sriyani;Todorovic, Slobodan M.
最近的数据表明，t型Ca2+通道是外周疼痛信号的放大器，但它们在感觉神经元紊乱（如与糖尿病相关的感觉神经元紊乱）中的作用尚不清楚。为了解决这个问题，我们对使用链脲佐菌素（N-[甲基亚硝基氨基油]- d -氨基葡萄糖）诱导的早期糖尿病神经病变的大鼠进行了行为学、免疫组织学、分子和电生理学的综合研究。我们发现，在糖尿病引起的疼痛发生的同时，L4-L5背根神经节（DRG）中等大小细胞的t型电流密度增加了两倍，并在稳态失活中发生去极化转移。这不仅与更突出的后去极化电位（ADPs）密切相关，而且还与细胞兴奋性增加密切相关，表现为糖尿病细胞的突发放电阈值比对照细胞低。t型电流和adp被镍有效抑制，l -半胱氨酸增强，表明CaV3.2 t型通道亚型被上调。对照和糖尿病ADPs DRG细胞分离素B4染色均呈阳性，但只有糖尿病细胞对辣椒素反应强烈，表明伤害功能增强。由于感觉神经元兴奋性的增加可能导致痛觉过敏和异常性疼痛等病理性疼痛感知，t型Ca2+电流的上调和Ca2+进入这些细胞的增强可能有助于糖尿病神经病变症状的发展。
Recent data indicate that T-type Ca2+ channels are amplifiers of peripheral pain signals, but their involvement in disorders of sensory neurons such as those associated with diabetes is poorly understood. To address this issue, we used a combination of behavioral, immunohistological, molecular, and electrophysiological studies in rats with streptozotocin (N-[methylnitrosocarbamoil]- D-glucosamine)induced early diabetic neuropathy. We found that, in parallel with the development of diabetes-induced pain, T-type current density increased by twofold in medium-size cells from L4-L5 dorsal root ganglia (DRG) with a depolarizing shift in steady-state inactivation. This not only correlated closely with more prominent afterdepolarizing potentials (ADPs) but also increased cellular excitability manifested as a lower threshold for burst firing in diabetic than in control cells. T-type currents and ADPs were potently inhibited by nickel and enhanced by L-cysteine, suggesting that the CaV3.2 T-type channel isoform was upregulated. Both control and diabetic DRG cells with ADPs stained positively for isolectin B4, but only diabetic cells responded robustly to capsaicin, suggesting enhanced nociceptive function. Because increased excitability of sensory neurons may result in such pathological perceptions of pain as hyperalgesia and allodynia, upregulation of T-type Ca2+ currents and enhanced Ca2+ entry into these cells could contribute to the development of symptoms in diabetic neuropathy.