Ca2+/calmodulin-dependent protein kinase II in the spinal cord contributes to neuropathic pain in a rat model of mononeuropathy
Ca2+/calmodulin-dependent protein kinase II in the spinal cord contributes to neuropathic pain in a rat model of mononeuropathy
复制标题
DOI：
10.1111/j.1460-9568.2005.04091.x
复制
发表时间：
2005-05-01
影响因子：
3.4
通讯作者：
Noguchi, K
中科院分区：
文献类型：
--
作者：
Dai, Y;Wang, H;Noguchi, K
已知Ca2+/钙调素依赖性蛋白激酶II （CaMKII）在中枢神经系统中具有活性依赖性神经元可塑性。为了研究脊髓CaMKII活性在周围神经损伤后神经性疼痛的发生和发展中的作用，我们使用了大鼠单神经病变动物模型，即慢性收缩损伤（CCI）模型。我们发现，CCI后3天，脊髓浅层的总CaMKII （tCaMKII）免疫反应性增加，这种增加持续了14天。磷酸化CaMKII的免疫反应性从CCI后1天开始增加，这是在tCaMKII上调之前。一种非选择性的n-甲基- d -天冬氨酸受体拮抗剂MK801显著降低了tCaMKII的增加和磷酸化CaMKII。此外，CCI手术前鞘内给予CaMKII抑制剂KN93可减轻热痛觉过敏和机械异常痛的发生。此外，KN93显著降低了福尔马林试验II期的伤害性行为。这些发现表明，脊髓神经元CaMKII的活性在外周神经损伤后升高，并可能参与中枢致敏。CaMKII的改变被认为是发生在脊髓神经元中的神经可塑性改变，导致神经性疼痛，这表明针对CaMKII的神经性疼痛的新疗法的发展潜力。
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is known to subserve activity-dependent neuronal plasticity in the central nervous system. To examine in vivo the implication of spinal CaMKII activity in the generation and development of neuropathic pain after peripheral nerve injury, we used an animal model of mononeuropathy, the chronic constriction injury (CCI) model, in the rat. We found that, 3 days after CCI, the total CaMKII (tCaMKII) immunoreactivity increased in the superficial laminae of the spinal cord and this increase continued for up to 14 days. The immunoreactivity of phosphorylated CaMKII showed an increase from 1 day after CCI, which preceded the up-regulation of tCaMKII. A non-selective N-methyl-D-aspartate receptor antagonist, MK801, significantly attenuated the increase of tCaMKII and phosphorylated CaMKII. Moreover, intrathecal administration of an inhibitor of CaMKII, KN93, before the CCI surgery attenuated the development of thermal hyperalgesia and mechanical allodynia. In addition, KN93 significantly reduced the nociceptive behavior in phase II of the formalin test. These findings demonstrate that the activity of CaMKII in spinal neurons is elevated after peripheral nerve injury and may be involved in central sensitization. The alteration of CaMKII is considered to be a neuroplastic change that occurs in spinal neurons that contributes to neuropathic pain, suggesting the potential for the development of novel therapeutics for neuropathic pain that target CaMKII.