Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Mol Pain. 2009 Dec 18;5:74. doi: 10.1186/1744-8069-5-74.
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 (alpha, beta, gamma1, gamma2, gamma3, delta, and epsilon) 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 (CK1epsilon) 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 CK1epsilon mRNA in the wild-type mice. Western blot analysis of the spinal cord identified the downregulation of CK1epsilon protein in the injured Cav2.2-/- mice, which is consistent with the data of microarray analysis. However, the expression of CK1epsilon 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 CK1epsilon protein in the dorsal root ganglion (DRG) and the spinal cord neurons. Both the percentage of CK1epsilon-positive neurons and the expression level of CK1epsilon 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 CK1epsilon plays important physiological roles in neuropathic pain signaling. Therefore CK1epsilon is a useful target for analgesic drug development.
神经病理性疼痛是一种由躯体感觉神经系统损伤或病理性改变引起的复杂慢性疼痛。神经病理性疼痛的特征是痛觉过敏、超敏反应和自发性疼痛。与神经病理性疼痛状态相关的这些异常仍然是一个重大的临床问题。然而，神经病理性疼痛发病机制的神经元机制很复杂，仍知之甚少。酪蛋白激酶 1 是一种丝氨酸/苏氨酸蛋白激酶，参与了广泛的信号转导活动，如细胞分化、增殖、凋亡、昼夜节律和膜转运。在哺乳动物中，CK1 家族由七个成员（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末端和羧基末端。
初步的 cDNA 微阵列分析显示，神经病理性疼痛抗性 N 型钙通道缺陷（Cav2.2-/-）小鼠脊髓中酪蛋白激酶 1 epsilon（CK1epsilon）mRNA 的表达在脊神经损伤后降低。同样的损伤对野生型小鼠 CK1epsilon mRNA 的表达没有影响。脊髓的 Western blot 分析确定 CK1epsilon 蛋白在受伤的 Cav2.2-/-小鼠中下调，这与微阵列分析的数据一致。然而，在受伤的野生型小鼠的脊髓中发现 CK1epsilon 蛋白的表达上调。免疫细胞化学分析显示，脊神经损伤改变了 CK1epsilon 蛋白在背根神经节（DRG）和脊髓神经元中的表达谱。神经病理性小鼠的 DRG 和脊髓中 CK1epsilon 阳性神经元的百分比和 CK1epsilon 蛋白的表达水平均增加。这些变化在受伤的 Cav2.2-/-小鼠的脊髓中得到逆转。此外，鞘内给予 CK1 抑制剂 IC261 对神经病理性小鼠产生明显的抗痛觉过敏和抗痛觉过敏作用。此外，IC261 降低了神经病理性小鼠初级传入纤维诱发的脊髓兴奋性反应。
这些结果表明，CK1epsilon 在神经病理性疼痛信号转导中发挥重要的生理作用。因此，CK1epsilon 是开发镇痛药物的一个有用靶点。
