Reversal of chronic inflammatory pain by acute inhibition of Ca2+/calmodulin-dependent protein kinase II
Reversal of chronic inflammatory pain by acute inhibition of Ca2+/calmodulin-dependent protein kinase II
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DOI：
10.1124/jpet.107.132167
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Wang, Zaijie Jim
中科院分区：
文献类型：
--
作者：
Luo, Fang;Yang, Cheng;Wang, Zaijie Jim
Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）是一种主要的蛋白激酶，能够调节许多离子通道和受体的活性。在本研究中，CaMKII在完全弗氏佐剂（CFA）诱导的炎性疼痛中的作用进行了研究。发现植入体内注射CFA诱导CaMKII（磷酸化CaMKII）的脊髓活性，其被CaMKII抑制剂KN 93 [[2-[N-（2-羟乙基）]N-（4-甲氧基苯磺酰基）]氨基-N-（4-氯肉桂酰基）-N-甲基苄胺）]阻断。KN 93预处理（i.t.）剂量依赖性地防止CFA诱导的热痛觉过敏和机械异常性疼痛的发展。KN 93急性治疗（i.t.）还剂量依赖性地逆转CFA诱导的热痛觉过敏和机械异常性疼痛。KN 93作用于30 min开始，至少持续2 ~ 4 h。KN 92（45 nmol i.t.）[2-[N-（4-甲氧基苯磺酰基）]氨基-N（4-氯肉桂酰基）-N-甲基苄胺]，一种KN 93的无活性类似物，对CFA诱导的CaMKII激活、异常性疼痛或痛觉过敏没有影响。此外，我们以前的研究确定三氟拉嗪，临床上使用的抗精神病药物，是一种有效的CaMKII抑制剂。研究证实了三氟拉嗪对CaMKII活性的抑制作用。此外，三氟拉嗪（i. p.）剂量依赖性逆转CFA诱导的机械异常性疼痛和热痛觉过敏。该药物口服时也有效。总之，我们的研究结果支持CaMKII在炎症性疼痛中的关键作用。阻断CaMKII或CaMKII介导的信号传导可能为治疗慢性疼痛提供新的治疗靶点。
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major protein kinase that is capable of regulating the activities of many ion channels and receptors. In the present study, the role of CaMKII in the complete Freund's adjuvant (CFA)-induced inflammatory pain was investigated. Intraplantarly injected CFA was found to induce spinal activity of CaMKII (phosphorylated CaMKII), which was blocked by KN93 [[2-[N-(2-hydroxyethyl)]N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine)], a CaMKII inhibitor. Pretreatment with KN93 (i.t.) dose-dependently prevented the development of CFA-induced thermal hyperalgesia and mechanical allodynia. Acute treatment with KN93 (i.t.) also dose-dependently reversed CFA-induced thermal hyperalgesia and mechanical allodynia. The action of KN93 started in 30 min and lasted for at least 2 to 4 h. KN92 (45 nmol i.t.) [2-[N-(4-methoxybenzenesulfonyl)]amino-N(4-chlorocinnamyl)-N-methylbenzylamine], an inactive analog of KN93, showed no effect on CFA-induced CaMKII activation, allodynia, or hyperalgesia. Furthermore, our previous studies identified trifluoperazine, a clinically used antipsychotic drug, to be a potent CaMKII inhibitor. Inhibition of CaMKII activity by trifluoperazine was confirmed in the study. In addition, trifluoperazine (i.p.) dose-dependently reversed CFA-induced mechanical allodynia and thermal hyperalgesia. The drug was also effectively when given orally. In conclusion, our findings support a critical role of CaMKII in inflammatory pain. Blocking CaMKII or CaMKII-mediated signaling may offer a novel therapeutic target for the treatment of chronic pain.