Neuropathic Sensitization of Behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice
Neuropathic Sensitization of Behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice
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DOI：
10.1016/s0960-9822(03)00084-8
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发表时间：
2003-02-18
期刊：
影响因子：
9.2
通讯作者：
Fleetwood-Walker, SM
中科院分区：
文献类型：
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作者：
Garry, EM;Moss, A;Fleetwood-Walker, SM
神经损伤引起的慢性疼痛对目前的止痛药有抵抗力。神经病理性疼痛的动物模型显示，脊髓中的神经元可塑性和行为反射敏化依赖于NMDA受体[1，2]。我们在脊髓背角发现了NMDA受体与多价接头蛋白PSD-95[3，4]的复合体，表明PSD-95在神经病理性反射敏化中起关键作用。使用表达截短形式的PSD-95分子的突变小鼠[5]，我们显示它们未能发展出在神经病理性疼痛的CCI模型中看到的依赖NMDA受体的痛觉过敏和超敏[6]，但注射福尔马林后正常的炎性伤害性行为。在CCI后的野生型小鼠中，CaM激酶II抑制剂减弱了行为反射的敏感化，在脊髓中检测到CaM激酶II的结构性(自动磷酸化)活性增加，并增加了磷酸化苏氨酸(286)CaM激酶II与NMDA受体NR2A/B亚单位的免疫共沉淀。在PSD-95突变小鼠中，这些变化中的每一种都被阻止，尽管存在CaM激酶II并可以被激活。在PSD-95突变小鼠中，CaM激酶II与NMDA受体对接和激活的中断可能是导致神经病理行为反射敏化缺失的原因。
Chronic pain due to nerve injury is resistant to current analgesics. Animal models of neuropathic pain show neuronal plasticity and behavioral reflex sensitization in the spinal cord that depend on the NMDA receptor [1, 2]. We reveal complexes of NMDA receptors with the multivalent adaptor protein PSD-95 [3, 4] in the dorsal horn of spinal cord and show that PSD-95 plays a key role in neuropathic reflex sensitization. Using mutant mice expressing a truncated form of the PSD-95 molecule [5], we show their failure to develop the NMDA receptor-dependent hyperalgesia and allodynia seen in the CCI model of neuropathic pain [6], but normal inflammatory nociceptive behavior following the injection of formalin. In wild-type mice following CCI, CaM kinase II inhibitors attenuate sensitization of behavioral reflexes, elevated constitutive (autophosphorylated) activity of CaM kinase II is detected in spinal cord, and increased amounts of phospho-Thr(286) CaM kinase II coimmunoprecipitate with NMDA receptor NR2A/B subunits. Each of these changes is prevented in PSD-95 mutant mice although CaM kinase II is present and can be activated. Disruption of CaM kinase II docking to the NMDA receptor and activation may be responsible for the lack of neuropathic behavioral reflex sensitization in PSD-95 mutant mice.