CaV3.2 T-type calcium channels in peripheral sensory neurons are important for mibefradil-induced reversal of hyperalgesia and allodynia in rats with painful diabetic neuropathy.
CaV3.2 T-type calcium channels in peripheral sensory neurons are important for mibefradil-induced reversal of hyperalgesia and allodynia in rats with painful diabetic neuropathy.
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DOI：
10.1371/journal.pone.0091467
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Jevtovic-Todorovic V
中科院分区：
文献类型：
--
作者：
Obradovic ALj;Hwang SM;Scarpa J;Hong SJ;Todorovic SM;Jevtovic-Todorovic V
我们最近发现，链脲佐菌素（STZ）注射在大鼠导致疼痛的周围糖尿病神经病变（PDN）的发展，伴随着增强的CaV3.2 T型钙电流（T电流）和超兴奋性背根神经节（DRG）神经元。在这里，我们使用了经典的外周作用T通道阻滞剂米贝拉地尔来检查CaV3.2 T通道作为治疗疼痛PDN的药理学靶点的作用。当腹膜内（i. p.）给药时，在临床相关剂量下，米贝拉地尔以剂量依赖性方式有效缓解STZ治疗的糖尿病大鼠的热、冷和机械超敏反应。我们还发现，与错配反义（MIS）治疗的糖尿病大鼠相比，CaV3.2反义（AS）治疗的糖尿病大鼠疼痛PDN显著减少。与米贝拉地尔（9 mg/kg i. p.）在MIS治疗的糖尿病大鼠中导致热、冷和机械超敏性的逆转，而在AS治疗的糖尿病大鼠中则没有，这表明米贝拉地尔和CaV 3.2 AS具有相同的细胞靶点。使用膜片钳记录从急性分离的DRG神经元，我们证明，米贝拉地尔同样阻断T-电流在糖尿病和健康大鼠的电压依赖性的方式，通过稳定非活性状态的T-通道。我们的结论是，抗痛觉过敏和抗异常性疼痛的mibefradil在PDN中至少部分介导的抑制外周伤害性感受器的CaV3.2通道。因此，外周作用的电压依赖性T通道阻滞剂可能是非常有用的治疗疼痛症状的PDN。
We recently showed that streptozotocin (STZ) injections in rats lead to the development of painful peripheral diabetic neuropathy (PDN) accompanied by enhancement of CaV3.2 T-type calcium currents (T-currents) and hyperexcitability in dorsal root ganglion (DRG) neurons. Here we used the classical peripherally acting T-channel blocker mibefradil to examine the role of CaV3.2 T-channels as pharmacological targets for treatment of painful PDN. When administered intraperitoneally (i.p.), at clinically relevant doses, mibefradil effectively alleviated heat, cold and mechanical hypersensitivities in STZ-treated diabetic rats in a dose-dependent manner. We also found that CaV3.2 antisense (AS)-treated diabetic rats exhibit a significant decrease in painful PDN compared with mismatch antisense (MIS)-treated diabetic rats. Co-treatment with mibefradil (9 mg/kg i.p.) resulted in reversal of heat, cold and mechanical hypersensitivity in MIS-treated but not in AS-treated diabetic rats, suggesting that mibefradil and CaV3.2 AS share the same cellular target. Using patch-clamp recordings from acutely dissociated DRG neurons, we demonstrated that mibefradil similarly blocked T-currents in diabetic and healthy rats in a voltage-dependent manner by stabilizing inactive states of T-channels. We conclude that antihyperalgesic and antiallodynic effects of mibefradil in PDN are at least partly mediated by inhibition of CaV3.2 channels in peripheral nociceptors. Hence, peripherally acting voltage-dependent T-channel blockers could be very useful in the treatment of painful symptoms of PDN.
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影响因子：
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