Protein kinases as potential targets for the treatment of pathological pain.
Protein kinases as potential targets for the treatment of pathological pain.
复制标题
DOI：
10.1007/978-3-540-33823-9_13
复制
发表时间：
2007
影响因子：
--
通讯作者：
R. Ji;Y. Kawasaki;Z. Zhuang;Yuqing Wen;Y.-Q. Zhang
中科院分区：
文献类型：
--
作者：
R. Ji;Y. Kawasaki;Z. Zhuang;Yuqing Wen;Y.-Q. Zhang
病理性疼痛或临床疼痛是指组织损伤引起的炎性疼痛和神经损伤引起的神经性疼痛，并且通常是慢性的。病理性疼痛是神经可塑性的表现，发生在周围神经系统（例如初级感觉伤害感受器）（称为外周敏化）和中枢神经系统（例如背角和脑神经元）（称为中枢敏化）中。我们对损伤引起的神经元可塑性的诱导和维持机制了解不足，阻碍了病理性疼痛的成功治疗。人类基因组编码 518 种蛋白激酶，代表最大的蛋白质家族之一。人们对开发用于治疗多种疾病的蛋白激酶抑制剂越来越感兴趣。尽管蛋白激酶并不被青睐作为镇痛药的靶点，但过去十年的研究已经证明这些激酶在调节神经元可塑性和疼痛敏化方面发挥着重要作用。多种蛋白激酶与强烈的伤害性刺激和损伤后的外周和中枢敏化有关。特别是，丝裂原激活蛋白激酶 (MAPK)，由细胞外信号调节激酶 (ERK)、p38 和 c-Jun N 末端激酶 (JNK) 组成，位于许多激酶的下游，并在初级感觉和背角神经元中被伤害感受活性、生长因子和炎症介质激活，通过翻译后、翻译和转录调节促进疼痛敏化的诱导和维持。损伤后脊髓胶质细胞（小胶质细胞和星形胶质细胞）中的 MAPK 也会被激活，导致炎症介质/神经活性物质的合成，作用于伤害性神经元，增强和延长疼痛敏感度。在不同的动物模型中，多种激酶的抑制已被证明可以减轻炎症和神经性疼痛。开发针对神经元和神经胶质细胞的特定蛋白激酶抑制剂将为开发治疗衰弱性慢性疼痛的新疗法提供线索。
Pathological pain or clinical pain refers to tissue injury-induced inflammatory pain and nerve injury-induced neuropathic pain and is often chronic. Pathological pain is an expression of neural plasticity that occurs both in the peripheral nervous system (e.g., primary sensory nociceptors), termed peripheral sensitization, and in the central nervous system (e.g., dorsal horn and brain neurons), termed central sensitization. Our insufficient understanding of mechanisms underlying the induction and maintenance of injury-induced neuronal plasticity hinders successful treatment for pathological pain.The human genome encodes 518 protein kinases, representing one of the largest protein families. There is growing interest in developing protein kinase inhibitors for the treatment of a number of diseases. Although protein kinases were not favored as targets for analgesics, studies in the last decade have demonstrated important roles of these kinases in regulating neuronal plasticity and pain sensitization. Multiple protein kinases have been implicated in peripheral and central sensitization following intense noxious stimuli and injuries. In particular, mitogen-activated protein kinases (MAPKs), consisting of extracellular signalregulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), are downstream to many kinases and are activated in primary sensory and dorsal horn neurons by nociceptive activity, growth factors and inflammatory mediators, contributing to the induction and maintenance of pain sensitization via posttranslational, translational, and transcriptional regulation. MAPKs are also activated in spinal glial cells (microglia and astrocytes) after injuries, leading to the synthesis of inflammatory mediators/neuroactive substances that act on nociceptive neurons, enhancing and prolonging pain sensitization. Inhibition of multiple kinases has been shown to attenuate inflammatory and neuropathic pain in different animal models. Development of specific inhibitors for protein kinases to target neurons and glial cells will shed light on the development of new therapies for debilitating chronic pain.