Ji R R, Kawasaki Y, Zhuang Z Y, Wen Y R, Zhang Y Q
Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, MRB 604, Boston, MA 02115, USA.
Handb Exp Pharmacol. 2007(177):359-89. doi: 10.1007/978-3-540-33823-9_13.
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 signal-regulated 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.
病理性疼痛或临床疼痛是指由组织损伤引起的炎性疼痛和神经损伤引起的神经性疼痛，通常为慢性疼痛。病理性疼痛是神经可塑性的一种表现，它既发生在外周神经系统（如初级感觉伤害感受器），称为外周敏化，也发生在中枢神经系统（如背角和脑神经元），称为中枢敏化。我们对损伤诱导的神经元可塑性的诱导和维持机制了解不足，这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，是最大的蛋白家族之一。开发用于治疗多种疾病的蛋白激酶抑制剂的兴趣日益浓厚。尽管蛋白激酶曾不被看好作为镇痛药的靶点，但过去十年的研究表明，这些激酶在调节神经元可塑性和疼痛敏化方面具有重要作用。多种蛋白激酶在强烈的伤害性刺激和损伤后的外周和中枢敏化中发挥作用。特别是，丝裂原活化蛋白激酶（MAPK）由细胞外信号调节激酶（ERK）、p38和c-Jun氨基末端激酶（JNK）组成，是许多激酶的下游靶点，并在初级感觉神经元和背角神经元中被伤害性活动、生长因子和炎性介质激活，通过翻译后、翻译和转录调控，促进疼痛敏化的诱导和维持。损伤后，MAPK在脊髓胶质细胞（小胶质细胞和星形胶质细胞）中也被激活，导致炎性介质/神经活性物质的合成，这些物质作用于伤害性神经元，增强并延长疼痛敏化。在不同的动物模型中，抑制多种激酶已被证明可减轻炎性和神经性疼痛。开发针对神经元和胶质细胞的蛋白激酶特异性抑制剂将为治疗使人衰弱的慢性疼痛的新疗法的开发提供线索。
