Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat
Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat
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DOI：
10.1074/jbc.m404167200
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发表时间：
2004-07-09
影响因子：
4.8
通讯作者：
Wiley, JW
中科院分区：
文献类型：
--
作者：
Hong, SS;Morrow, TJ;Wiley, JW
糖尿病性神经病变是周围神经病变的常见形式，但对这种疾病中引起疼痛的机制知之甚少。电压门控河豚毒素耐药（TTX-R）钠通道的表达和功能的改变与神经性疼痛的动物模型（包括糖尿病神经病变模型）有关。我们研究了糖尿病大鼠发病后4-8周，背根神经节（DRG）神经元TTX-S和TTX-R钠通道的表达和功能，以及对热痛觉过敏和机械异常性疼痛的反应。糖尿病大鼠表现出逃避无害的机械压力（异常性疼痛）的阈值显着降低，并减少从有害的热刺激（痛觉过敏）撤回的潜伏期。TTX-S和TTX-R钠电流在分离自糖尿病大鼠的小DRG神经元中显著增加。这些电流的电压依赖性激活和稳态失活曲线负移。在糖尿病大鼠神经元上，由快、慢电压斜坡诱发的TTX-S电流均显著增加。免疫印迹和免疫荧光染色显示糖尿病大鼠Na（v）1.3（TTX-S）和Na（v）1.7（TTX-S）的表达显著增加，Na（v）1.6（TTX-S）和Na（v）1.8（TTX-R）的表达显著减少。Na（v）1.6和Na（v）1.8的丝氨酸/苏氨酸磷酸化水平在糖尿病时增加。此外，在糖尿病大鼠的DRG中观察到Na（v）1.6和Na（v）1.7的酪氨酸磷酸化增加。这些结果表明，TTX-S和TTX-R钠通道发挥重要作用，并涉及丝氨酸/苏氨酸和酪氨酸位点的钠通道的差异磷酸化有助于疼痛性糖尿病神经病变。
Diabetic neuropathy is a common form of peripheral neuropathy, yet the mechanisms responsible for pain in this disease are poorly understood. Alterations in the expression and function of voltage-gated tetrodotoxin-resistant (TTX-R) sodium channels have been implicated in animal models of neuropathic pain, including models of diabetic neuropathy. We investigated the expression and function of TTX-sensitive (TTX-S) and TTX-R sodium channels in dorsal root ganglion (DRG) neurons and the responses to thermal hyperalgesia and mechanical allodynia in streptozotocin-treated rats between 4-8 weeks after onset of diabetes. Diabetic rats demonstrated a significant reduction in the threshold for escape from innocuous mechanical pressure ( allodynia) and a reduction in the latency to withdrawal from a noxious thermal stimulus ( hyperalgesia). Both TTX-S and TTX-R sodium currents increased significantly in small DRG neurons isolated from diabetic rats. The voltage-dependent activation and steady-state inactivation curves for these currents were shifted negatively. TTX-S currents induced by fast or slow voltage ramps increased markedly in neurons from diabetic rats. Immunoblots and immunofluorescence staining demonstrated significant increases in the expression of Na(v)1.3 (TTX-S) and Na(v)1.7 (TTX-S) and decreases in the expression of Na(v)1.6 (TTX-S) and Na(v)1.8 (TTX-R) in diabetic rats. The level of serine/threonine phosphorylation of Na(v)1.6 and Na(v)1.8 increased in response to diabetes. In addition, increased tyrosine phosphorylation of Na(v)1.6 and Na(v)1.7 was observed in DRGs from diabetic rats. These results suggest that both TTX-S and TTX-R sodium channels play important roles and that differential phosphorylation of sodium channels involving both serine/threonine and tyrosine sites contributes to painful diabetic neuropathy.