Spinal Mitogen-Activated Protein Kinase Phosphatase-3 (MKP-3) is Necessary for the Normal Resolution of Mechanical Allodynia in a Mouse Model of Acute Postoperative Pain
Spinal Mitogen-Activated Protein Kinase Phosphatase-3 (MKP-3) is Necessary for the Normal Resolution of Mechanical Allodynia in a Mouse Model of Acute Postoperative Pain
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DOI：
10.1523/jneurosci.5605-12.2013
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发表时间：
2013-10-23
影响因子：
5.3
通讯作者：
Romero-Sandoval, E. Alfonso
中科院分区：
文献类型：
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作者：
Saha, Madhurima;Skopelja, Sladjana;Romero-Sandoval, E. Alfonso
驱动急性术后疼痛正常消退的机制尚未完全了解。我们假设一个主要的脊髓丝裂原活化蛋白激酶（MAPK）调节剂，MAPK磷酸酶（MKP）-3，在术后疼痛的决议中的关键作用。我们使用野生型和MKP-3基因敲除（KO）小鼠，急性术后疼痛的爪切口模型，以及行为和分子生物学实验。我们在缺乏MKP-3的小鼠中观察到持续的机械性异常性疼痛（术后第21天），同时在术后第12天脊髓p38和细胞外信号调节激酶（ERK）-12的持续磷酸化，而在野生型小鼠中MAPK磷酸化和异常性疼痛在术后第7天消退。在MKP-3 KO小鼠中，脊髓p-ERK主要在神经元和小胶质细胞中表达，而脊髓p-p38主要在小胶质细胞中表达，并且它们的选择性药理学抑制减少了在这些小鼠中观察到的持续性异常性疼痛。我们的研究结果强烈表明，MKP-3的失调阻止急性术后疼痛的自发消退，并通过脊髓中持续的神经元和小胶质细胞MAPK磷酸化驱动其转变为持续性疼痛。
The mechanisms that drive the normal resolution of acute postoperative pain are not completely understood. We hypothesize a pivotal role of a major spinal mitogen-activated protein kinase (MAPKs) regulator, MAPK phosphatase (MKP)-3, in the resolution of postoperative pain. We used wild-type and MKP-3 knock-out (KO) mice, a paw incision model of acute postoperative pain, and behavioral and molecular biology experiments. We observed persistent mechanical allodynia in mice lacking MKP-3 (postoperative day 21), concurrently with persistent phosphorylation of spinal p38 and extracellular signal-regulated kinases (ERK)-1/2 on postoperative day 12, while both MAPK phosphorylation and allodynia resolved on postoperative day 7 in wild-type mice. Spinal p-ERK was expressed mainly in neurons and microglia, while spinal p-p38 was expressed mostly in microglia in MKP-3 KO mice, and their selective pharmacological inhibition reduced the persistent allodynia observed in these mice. Our findings strongly suggest that dysregulation of MKP-3 prevents spontaneous resolution of acute postoperative pain and drives its transition to persistent pain via persistent neuronal and microglial MAPK phosphorylation in the spinal cord.