GABAergic Inhibition Regulated Pain Sensitization through STEP61 Signaling in Spinal Dorsal Horn of Mice
GABAergic Inhibition Regulated Pain Sensitization through STEP61 Signaling in Spinal Dorsal Horn of Mice
复制标题
GABA能抑制通过STEP61信号调节小鼠脊髓背角的疼痛敏化
DOI：
10.1097/aln.0000000000000532
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发表时间：
2015-03-01
期刊：
影响因子：
8.8
通讯作者：
Hu, Xiao-Dong
中科院分区：
文献类型：
--
作者：
Li, Lu;Shi, Lei;Hu, Xiao-Dong
背景资料：减少氨基丁酸（GABA）A型受体介导的抑制作用长期以来一直涉及脊髓致敏的伤害性反应。然而，它在很大程度上是未知的，在脊髓背角神经元的信号级联反应的减少抑制触发pain hypersensitivity.Methods：GABA能抑制操纵鞘内应用GABA A型受体拮抗剂荷包牡丹碱在完整的小鼠或GABA A型受体激动剂蝇蕈醇在完全弗氏佐剂注射小鼠。免疫印迹、免疫共沉淀、免疫组织化学和行为学测试被用于探索改变的GABA能tone.Results下游的信号通路：研究数据显示，纹状体富集蛋白磷酸酶的61-kD异构体（STEP 61）是一个关键分子，中继GABA能神经传递的信号。作者发现STEP 61在背角神经元中高度表达。在生理条件下，STEP 61与细胞外信号调节激酶和Src家族蛋白酪氨酸激酶成员Fyn（参与脊髓致敏的两种关键激酶）进行紧张性相互作用并负向控制其活性。一旦GABA能抑制受损，STEP 61与其底物的相互作用基本上受到干扰，允许细胞外信号调节激酶和Fyn的激活（n = 4至6）。细胞外信号调节激酶和Fyn的高活性，沿着STEP 61的失调，引起谷氨酸受体（n = 6）的含GluN 2B亚基的N-甲基-d-天冬氨酸亚型的酪氨酸磷酸化和突触积累，导致GluN 2B受体依赖性疼痛超敏反应。过表达野生型STEP 61恢复其酶活性显着阻断机械异常性疼痛引起的荷包牡丹碱，更重要的是，减轻慢性炎性疼痛（n = 6在每个group.Conclusion：这些数据确定STEP 61作为一个关键的中介GABA能抑制调节疼痛敏化。
Background: The reduction of -aminobutyric acid (GABA) type A receptor-mediated inhibition has long been implicated in spinal sensitization of nociceptive responses. However, it is largely unknown which signaling cascades in spinal dorsal horn neurons are initiated by the reduced inhibition to trigger pain hypersensitivity.Methods: GABAergic inhibition was manipulated by intrathecal application of GABA type A receptor antagonist bicuculline in intact mice or by GABA type A receptor agonist muscimol in complete Freund's adjuvant-injected mice. Immunoblotting, coimmunoprecipitation, immunohistochemistry, and behavioral tests were used to explore the signaling pathways downstream of the altered GABAergic tone.Results: The study data revealed that the 61-kD isoform of striatal-enriched protein phosphatase (STEP61) was a key molecule that relayed the signals from GABAergic neurotransmission. The authors found that STEP61 was highly expressed in dorsal horn neurons. Under physiological conditions, STEP61 tonically interacted with and negatively controlled the activities of extracellular signal-regulated kinase and Src-family protein tyrosine kinases member Fyn, two critical kinases involved in spinal sensitization. Once GABAergic inhibition was impaired, STEP61 interaction with its substrates was substantially disturbed, allowing for activation of extracellular signal-regulated kinase and Fyn (n = 4 to 6). The hyperactivities of extracellular signal-regulated kinase and Fyn, along with STEP61 dysregulation, caused the tyrosine phosphorylation and synaptic accumulation of GluN2B subunit-containing N-methyl-d-aspartate subtype of glutamate receptors (n = 6), leading to GluN2B receptor-dependent pain hypersensitivity. Overexpression of wild-type STEP61 to resume its enzymatic activity significantly blocked the mechanical allodynia evoked by bicuculline and more importantly, alleviated chronic inflammatory pain (n = 6 in each group).Conclusion: These data identified STEP61 as a key intermediary for GABAergic inhibition to regulate pain sensitization.