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两种结构不同的酪蛋白激酶 1（CK1）抑制剂缓解炎性痛小鼠模型的行为过敏。

Alleviation of behavioral hypersensitivity in mouse models of inflammatory pain with two structurally different casein kinase 1 (CK1) inhibitors.

机构信息

Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.

出版信息

Mol Pain. 2014 Mar 10;10:17. doi: 10.1186/1744-8069-10-17.

DOI:10.1186/1744-8069-10-17
PMID:24612480
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4008364/
Abstract

BACKGROUND

The phylogenetically highly conserved CK1 protein kinases consisting of at least seven isoforms form a distinct family within the eukaryotic protein kinases. CK1 family members play crucial roles in a wide range of signaling activities. However, the functional role of CK1 in somatosensory pain signaling has not yet been fully understood. The aim of this study was to clarify the role of CK1 in the regulation of inflammatory pain in mouse carrageenan and complete Freund's adjuvant (CFA) models.

RESULTS

We have used two structurally different CK1 inhibitors, TG003 and IC261. TG003, which was originally identified as a cdc2-like kinase inhibitor, had potent inhibitory effects on CK1 isoforms in vitro and in cultured cells. Intrathecal injection of either TG003 (1-100 pmol) or IC261 (0.1-1 nmol) dose-dependently decreased mechanical allodynia and thermal hyperalgesia induced by carrageenan or CFA. Bath-application of either TG003 (1 μM) or IC261 (1 μM) had only marginal effects on spontaneous excitatory postsynaptic currents (sEPSCs) recorded in the substantia gelatinosa neurons of control mice. However, both compounds decreased the frequency of sEPSCs in both inflammatory pain models.

CONCLUSIONS

These results suggest that CK1 plays an important pathophysiological role in spinal inflammatory pain transmission, and that inhibition of the CK1 activity may provide a novel strategy for the treatment of inflammatory pain.

摘要

背景

由至少七种同工型组成的进化上高度保守的 CK1 蛋白激酶在真核蛋白激酶中形成一个独特的家族。CK1 家族成员在广泛的信号转导活动中发挥着至关重要的作用。然而，CK1 在躯体感觉疼痛信号转导中的功能作用尚未完全理解。本研究旨在阐明 CK1 在小鼠角叉菜胶和完全弗氏佐剂（CFA）模型中炎症性疼痛调节中的作用。

结果

我们使用了两种结构不同的 CK1 抑制剂 TG003 和 IC261。TG003 最初被鉴定为一种 cdc2 样激酶抑制剂，对体外和培养细胞中的 CK1 同工型具有很强的抑制作用。鞘内注射 TG003（1-100 pmol）或 IC261（0.1-1 nmol）均可剂量依赖性地减轻角叉菜胶或 CFA 引起的机械性痛觉过敏和热痛觉过敏。TG003（1 μM）或 IC261（1 μM）的浴应用对对照组小鼠胶状质神经元记录的自发兴奋性突触后电流（sEPSC）仅有轻微影响。然而，这两种化合物都降低了两种炎症性疼痛模型中 sEPSC 的频率。

结论

这些结果表明，CK1 在脊髓炎症性疼痛传递中起着重要的病理生理作用，抑制 CK1 活性可能为治疗炎症性疼痛提供一种新策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/777f/4008364/aa9a4621f282/1744-8069-10-17-7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/777f/4008364/994626b708f7/1744-8069-10-17-1.jpg
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