Acute Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice
Acute Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice
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DOI：
10.1124/jpet.109.152165
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发表时间：
2009-08-01
影响因子：
3.5
通讯作者：
Wang, Zaijie Jim
中科院分区：
文献类型：
--
作者：
Chen, Yan;Luo, Fang;Wang, Zaijie Jim
目前关于Ca2+/钙调素依赖性蛋白激酶II （CaMKII）在神经性疼痛中的作用的有限数据是相互矛盾的。在本研究中，我们在实验性单神经病变的啮齿动物模型中验证了CaMKII是维持神经性疼痛所必需的假设。脊髓神经L-5/L-6结扎（SNL）可增加同侧（而非对侧）CaMKII （pCaMKII）的脊髓活性。CaMKII抑制剂2-[N-（2-羟乙基）-N（4-甲氧基苯磺基）]氨基-N-（4-氯肉桂基）- Nmethylbenzylamine) (KN93)（鞘内注射）阻断了这种作用。KN93剂量依赖性逆转snl诱导的热痛觉过敏和机械异常痛的急性治疗。KN93的作用至少持续2至4小时。KN93的无活性类似物2-[N（4-甲氧基苯磺酰）]氨基-N-（4-氯肉桂酰）-N-甲基苄胺（KN92） （45 nmol i.t）对snl诱导的CaMKII激活、异常性疼痛或痛觉过敏没有影响。我们进一步检查了临床上使用的抗精神病药物三氟拉嗪的药理学作用，在这些试验中我们发现三氟拉嗪是一种有效的CaMKII抑制剂。在使用最高剂量的小鼠中，三氟拉嗪（腹腔或口服）剂量依赖性地逆转snl诱导的机械异常性疼痛、热痛觉过敏和CaMKII激活，而不引起运动障碍。总之，我们的研究结果支持CaMKII在神经性疼痛中的关键作用。阻断CaMKII或CaMKII介导的信号可能为神经性疼痛的治疗提供新的治疗靶点。
The limited data that currently exist for the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in neuropathic pain are conflicting. In the present study, we tested the hypothesis that CaMKII is required for the maintenance of neuropathic pain in a rodent model of experimental mononeuropathy. Spinal nerve L-5/L-6 ligation (SNL) was found to increase the spinal activity of CaMKII (pCaMKII) on the ipsilateral (but not contralateral) side. This effect was blocked by 2-[N-(2-hydroxyethyl)-N( 4-methoxybenzenesulfonyl)] amino-N-(4-chlorocinnamyl)--Nmethylbenzylamine) (KN93) (intrathecal injection), a CaMKII inhibitor. Acute treatment with KN93 dose-dependently reversed SNL-induced thermal hyperalgesia and mechanical allodynia. The action of KN93 lasted for at least 2 to 4 h. 2-[N( 4-Methoxybenzenesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (KN92) (45 nmol i.t.), an inactive analog of KN93, showed no effect on SNL-induced CaMKII activation, allodynia, or hyperalgesia. We further examined the pharmacologic action of trifluoperazine, a clinically used antipsychotic drug that we found to be a potent CaMKII inhibitor in these assays. Trifluoperazine (administered intraperitoneally or by mouth) dose-dependently reversed SNL-induced mechanical allodynia, thermal hyperalgesia, and CaMKII activation without causing locomotor impairment in mice at the highest doses used. In conclusion, our findings support a critical role of CaMKII in neuropathic pain. Blocking CaMKII or CaMKII-mediated signaling may offer a novel therapeutic target for the treatment of neuropathic pain.