Phospholipase C-related but catalytically inactive protein modulates pain behavior in a neuropathic pain model in mice.
Phospholipase C-related but catalytically inactive protein modulates pain behavior in a neuropathic pain model in mice.
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DOI：
10.1186/1744-8069-9-23
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发表时间：
2013-05-02
期刊：
影响因子：
3.3
通讯作者：
Kanematsu T
中科院分区：
文献类型：
--
作者：
Kitayama T;Morita K;Sultana R;Kikushige N;Mgita K;Ueno S;Hirata M;Kanematsu T
一种肌醇1，4，5-三磷酸结合蛋白，包括两种亚型，称为PRIP-1和PRIP-2，被鉴定为GABAA受体转运的新调节剂。据报道，幼稚PRIP-1基因敲除小鼠具有痛觉过敏反应。为了确定PRIP参与疼痛感觉，在PRIP-1和PRIP-2双敲除（DKO）小鼠中在部分坐骨神经结扎（PSNL）之前和之后进行后爪缩回试验。我们发现，幼稚DKO小鼠表现出正常的疼痛敏感性。然而，经历PSNL手术的DKO小鼠显示出增加的同侧缩爪阈值。为了进一步研究PRIP-1 KO和DKO小鼠中的反向表型，我们产生了在脊髓中具有特异性siRNA介导的PRIP敲低的小鼠。与KO小鼠的表型一致，PRIP-1敲除小鼠显示异常性疼痛，而具有PSNL的PRIP双敲除（DKD）小鼠显示疼痛相关行为减少。这表明脊髓中两种PRIPs的表达减少诱导对疼痛感觉的抵抗。GABAA受体亚单位表达模式在PRIP-1 KO和DKO脊髓之间相似，而控制神经元兴奋和抑制平衡的K+-Cl-协同转运蛋白2（KCC 2）的表达在DKO小鼠中显著上调。此外，在DKD PSNL模型中，一种由多巴胺诱导的KCC 2抑制表现出从无痛到疼痛感觉的改变的表型。PRIPs的抑制表达诱导脊髓中KCC 2的表达升高，导致DKO小鼠中伤害感受的抑制和神经性疼痛的改善。
An inositol 1,4,5-trisphosphate binding protein, comprising 2 isoforms termed PRIP-1 and PRIP-2, was identified as a novel modulator for GABAA receptor trafficking. It has been reported that naive PRIP-1 knockout mice have hyperalgesic responses. To determine the involvement of PRIP in pain sensation, a hind paw withdrawal test was performed before and after partial sciatic nerve ligation (PSNL) in PRIP-1 and PRIP-2 double knockout (DKO) mice. We found that naive DKO mice exhibited normal pain sensitivity. However, DKO mice that underwent PSNL surgery showed increased ipsilateral paw withdrawal threshold. To further investigate the inverse phenotype in PRIP-1 KO and DKO mice, we produced mice with specific siRNA-mediated knockdown of PRIPs in the spinal cord. Consistent with the phenotypes of KO mice, PRIP-1 knockdown mice showed allodynia, while PRIP double knockdown (DKD) mice with PSNL showed decreased pain-related behavior. This indicates that reduced expression of both PRIPs in the spinal cord induces resistance towards a painful sensation. GABAA receptor subunit expression pattern was similar between PRIP-1 KO and DKO spinal cord, while expression of K+-Cl--cotransporter-2 (KCC2), which controls the balance of neuronal excitation and inhibition, was significantly upregulated in DKO mice. Furthermore, in the DKD PSNL model, an inhibitor-induced KCC2 inhibition exhibited an altered phenotype from painless to painful sensations. Suppressed expression of PRIPs induces an elevated expression of KCC2 in the spinal cord, resulting in inhibition of nociception and amelioration of neuropathic pain in DKO mice.
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影响因子：
4.1
作者：
Takeuchi, H;Kanematsu, T;Hirata, M
通讯作者：
Hirata, M
影响因子：
4.8
作者：
Yoshimura, K;Takeuchi, H;Hirata, M
通讯作者：
Hirata, M
影响因子：
7.4
作者：
SELTZER, Z;DUBNER, R;SHIR, Y
通讯作者：
SHIR, Y
影响因子：
3.3
作者：
Migita K;Tomiyama M;Yamada J;Fukuzawa M;Kanematsu T;Hirata M;Ueno S
通讯作者：
Ueno S
影响因子：
4.1
作者：
Kanematsu, T;Misumi, Y;Hirata, M
通讯作者：
Hirata, M