Casein Kinase II Inhibition Reverses Pain Hypersensitivity and Potentiated Spinal N-Methyl-d-aspartate Receptor Activity Caused by Calcineurin Inhibitor
Casein Kinase II Inhibition Reverses Pain Hypersensitivity and Potentiated Spinal N-Methyl-d-aspartate Receptor Activity Caused by Calcineurin Inhibitor
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DOI：
10.1124/jpet.113.212563
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发表时间：
2014-05
期刊：
影响因子：
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通讯作者：
Yi-Min Hu;Shaorui Chen;Hong Chen;H. Pan
中科院分区：
文献类型：
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作者：
Yi-Min Hu;Shaorui Chen;Hong Chen;H. Pan
临床上使用的钙调磷酸酶抑制剂，包括他克莫司（FK506）和环孢素A，可诱发钙调磷酸酶抑制剂诱发的疼痛综合征（CIPS），其特征为剧烈疼痛和疼痛超敏反应。脊髓背角突触 N-甲基-d-天冬氨酸受体 (NMDAR) 活性的增加在 CIPS 的发生中起着至关重要的作用。酪蛋白激酶 II (CK2) 是一种丝氨酸/苏氨酸蛋白激酶，可以调节大脑中的突触 NMDAR 活性。在这项研究中，我们确定了脊髓 CK2 是否参与大鼠全身施用 FK506 引起的 NMDAR 活性增加和疼痛超敏反应。 FK506 治疗导致初级传入刺激诱发的 NMDAR 介导的兴奋性突触后电流 (EPSC) 的振幅以及脊髓背角神经元的微型 EPSC 的频率大幅增加。使用 5,6-二氯-1-β-d-呋喃核糖基苯并咪唑 (DRB) 或 4,5,6,7-四溴苯并三唑 (TBB) 抑制 CK2，使 FK506 治疗的大鼠背角神经元诱发的 NMDAR-EPSC 振幅完全正常化。此外，DRB 或 TBB 显着减弱了向 FK506 处理的大鼠的背角神经元喷射 N-甲基-D-天冬氨酸所引起的 NMDAR 电流的幅度。此外，DRB 或 TBB 治疗显着降低了 FK506 治疗增加的脊髓背角神经元微型 EPSC 的频率。此外，鞘内注射 DRB 或 TBB 可以剂量依赖性地逆转 FK506 治疗大鼠的触觉异常性疼痛和机械性痛觉过敏。总的来说，我们的研究结果表明，CK2 抑制消除了由钙调神经磷酸酶抑制剂引起的疼痛超敏反应，并增加了脊髓中突触前和突触后 NMDAR 活性。 CK2抑制剂可能代表治疗CIPS的新治疗选择。
Clinically used calcineurin inhibitors, including tacrolimus (FK506) and cyclosporine A, can induce calcineurin inhibitor-induced pain syndrome (CIPS), which is characterized as severe pain and pain hypersensitivity. Increased synaptic N-methyl-d-aspartate receptor (NMDAR) activity in the spinal dorsal horn plays a critical role in the development of CIPS. Casein kinase II (CK2), a serine/threonine protein kinase, can regulate synaptic NMDAR activity in the brain. In this study, we determined whether spinal CK2 is involved in increased NMDAR activity and pain hypersensitivity caused by systemic administration of FK506 in rats. FK506 treatment caused a large increase in the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) evoked by primary afferent stimulation and in the frequency of miniature EPSCs of spinal dorsal horn neurons. CK2 inhibition with either 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) or 4,5,6,7-tetrabromobenzotriazole (TBB) completely normalized the amplitude of evoked NMDAR-EPSCs of dorsal horn neurons in FK506-treated rats. In addition, DRB or TBB significantly attenuated the amplitude of NMDAR currents elicited by puff application of N-methyl-D-aspartate to dorsal horn neurons in FK506-treated rats. Furthermore, treatment with DRB or TBB significantly reduced the frequency of miniature EPSCs of spinal dorsal horn neurons increased by FK506 treatment. In addition, intrathecal injection of DRB or TBB dose-dependently reversed tactile allodynia and mechanical hyperalgesia in FK506-treated rats. Collectively, our findings indicate that CK2 inhibition abrogates pain hypersensitivity and increased pre- and postsynaptic NMDAR activity in the spinal cord caused by calcineurin inhibitors. CK2 inhibitors may represent a new therapeutic option for the treatment of CIPS.