Upregulation of casein kinase 1epsilon in dorsal root ganglia and spinal cord after mouse spinal nerve injury contributes to neuropathic pain.
Upregulation of casein kinase 1epsilon in dorsal root ganglia and spinal cord after mouse spinal nerve injury contributes to neuropathic pain.
复制标题
DOI：
10.1186/1744-8069-5-74
复制
发表时间：
2009-12-18
期刊：
影响因子：
3.3
通讯作者：
Tanabe T
中科院分区：
文献类型：
--
作者：
Sakurai E;Kurihara T;Kouchi K;Saegusa H;Zong S;Tanabe T
神经病理性疼痛是由躯体感觉神经系统的损伤或病理变化产生的复杂慢性疼痛。神经病理性疼痛的特征是异常性疼痛、痛觉过敏和自发性疼痛。这种与神经性疼痛状态相关的异常仍然是一个重要的临床问题。然而，神经病理性疼痛的发病机制是复杂的，仍然知之甚少。酪蛋白激酶1是一种丝氨酸/苏氨酸蛋白激酶，并且已经涉及广泛的信号传导活动，例如细胞分化、增殖、凋亡、昼夜节律和膜转运。在哺乳动物中，CK 1家族由7个成员（α、β、γ1、γ2、γ3、δ和ε）组成，具有高度保守的激酶结构域和不同的氨基和羧基末端。初步的cDNA微阵列分析显示，神经病理性疼痛耐受性N型钙通道缺陷（Cav2.2-/-）小鼠脊髓中酪蛋白激酶1 ε（CK 1 ε）mRNA的表达因脊神经损伤而降低。相同的损伤对野生型小鼠CK 1 ε mRNA的表达无影响。Western blot检测脊髓损伤后Cav 2. 2-/-小鼠CK 1 ε蛋白表达下调，与基因芯片检测结果一致。然而，在损伤的野生型小鼠脊髓中发现CK 1 ε蛋白的表达上调。免疫细胞化学分析显示，脊神经损伤后，背根神经节（DRG）和脊髓神经元中CK 1 ε蛋白表达发生改变。神经病小鼠DRG和脊髓中CK 1 ε阳性神经元的百分比和CK 1 ε蛋白的表达水平均增加。这些变化在受损Cav2.2-/-小鼠的脊髓中被逆转。此外，鞘内给予CK 1抑制剂IC 261对神经病小鼠产生显著的抗异常性疼痛和抗痛觉过敏作用。此外，初级传入纤维诱发的脊髓兴奋性反应在神经病小鼠减少IC 261。这些结果表明，CK 1 ε在神经病理性疼痛信号传导中起重要的生理作用。因此，CK 1 ε是镇痛药物开发的有用靶点。
Neuropathic pain is a complex chronic pain generated by damage to, or pathological changes in the somatosensory nervous system. Characteristic features of neuropathic pain are allodynia, hyperalgesia and spontaneous pain. Such abnormalities associated with neuropathic pain state remain to be a significant clinical problem. However, the neuronal mechanisms underlying the pathogenesis of neuropathic pain are complex and still poorly understood. Casein kinase 1 is a serine/threonine protein kinase and has been implicated in a wide range of signaling activities such as cell differentiation, proliferation, apoptosis, circadian rhythms and membrane transport. In mammals, the CK1 family consists of seven members (α, β, γ1, γ2, γ3, δ, and ε) with a highly conserved kinase domain and divergent amino- and carboxy-termini. Preliminary cDNA microarray analysis revealed that the expression of the casein kinase 1 epsilon (CK1ε) mRNA in the spinal cord of the neuropathic pain-resistant N- type Ca2+ channel deficient (Cav2.2-/-) mice was decreased by the spinal nerve injury. The same injury exerted no effects on the expression of CK1ε mRNA in the wild-type mice. Western blot analysis of the spinal cord identified the downregulation of CK1ε protein in the injured Cav2.2-/- mice, which is consistent with the data of microarray analysis. However, the expression of CK1ε protein was found to be up-regulated in the spinal cord of injured wild-type mice. Immunocytochemical analysis revealed that the spinal nerve injury changed the expression profiles of CK1ε protein in the dorsal root ganglion (DRG) and the spinal cord neurons. Both the percentage of CK1ε-positive neurons and the expression level of CK1ε protein were increased in DRG and the spinal cord of the neuropathic mice. These changes were reversed in the spinal cord of the injured Cav2.2-/- mice. Furthermore, intrathecal administration of a CK1 inhibitor IC261 produced marked anti-allodynic and anti-hyperalgesic effects on the neuropathic mice. In addition, primary afferent fiber-evoked spinal excitatory responses in the neuropathic mice were reduced by IC261. These results suggest that CK1ε plays important physiological roles in neuropathic pain signaling. Therefore CK1ε is a useful target for analgesic drug development.
登录
查看更多内容
影响因子：
7.4
作者：
Fukuoka, T;Tokunaga, A;Noguchi, K
通讯作者：
Noguchi, K
DOI：
10.1073/pnas.0306880101
发表时间：
2004-08-10
影响因子：
11.1
作者：
Caenepeel, S;Charydczak, G;Manning, G
通讯作者：
Manning, G
影响因子：
3.5
作者：
Kondo, Daisuke;Saegusa, Hironao;Tanabe, Tsutomu
通讯作者：
Tanabe, Tsutomu
影响因子：
5
作者：
Kondo, Daisuke;Yabe, Ritsuko;Tanabe, Tsutomu
通讯作者：
Tanabe, Tsutomu
影响因子：
2.9
作者：
Ikeda, H;Ryu, PD;Murase, K
通讯作者：
Murase, K