Ji Ru-Rong, Strichartz Gary
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sci STKE. 2004 Sep 21;2004(252):reE14. doi: 10.1126/stke.2522004re14.
Damage to the nervous system can cause neuropathic pain, which is in general poorly treated and involves mechanisms that are incompletely known. Currently available animal models for neuropathic pain mainly involve partial injury of peripheral nerves. Multiple inflammatory mediators released from damaged tissue not only acutely excite primary sensory neurons in the peripheral nervous system, producing ectopic discharge, but also lead to a sustained increase in their excitability. Hyperexcitability also develops in the central nervous system (for instance, in dorsal horn neurons), and both peripheral and spinal elements contribute to neuropathic pain, so that spontaneous pain may occur or normally innocuous stimuli may produce pain. Inflammatory mediators and aberrant neuronal activity activate several signaling pathways [including protein kinases A and C, calcium/calmodulin-dependent protein kinase, and mitogen-activated protein kinases (MAPKs)] in primary sensory and dorsal horn neurons that mediate the induction and maintenance of neuropathic pain through both posttranslational and transcriptional mechanisms. In particular, peripheral nerve lesions result in activation of MAPKs (p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase) in microglia or astrocytes in the spinal cord, or both, leading to the production of inflammatory mediators that sensitize dorsal horn neurons. Activity of dorsal horn neurons, in turn, enhances activation of spinal glia. This neuron-glia interaction involves positive feedback mechanisms and is likely to enhance and prolong neuropathic pain even in the absence of ongoing peripheral external stimulation or injury. The goal of this review is to present evidence for signaling cascades in these cell types that not only will deepen our understanding of the genesis of neuropathic pain but also may help to identify new targets for pharmacological intervention.
神经系统损伤可导致神经性疼痛,这种疼痛一般难以治疗,其涉及的机制也尚未完全明确。目前可用的神经性疼痛动物模型主要涉及外周神经的部分损伤。受损组织释放的多种炎症介质不仅会急性激活外周神经系统中的初级感觉神经元,产生异位放电,还会导致其兴奋性持续增加。中枢神经系统(例如背角神经元)也会出现兴奋性过高的情况,外周和脊髓因素均会导致神经性疼痛,从而可能出现自发痛,或正常情况下无害的刺激也可能产生疼痛。炎症介质和异常的神经元活动会激活初级感觉神经元和背角神经元中的多种信号通路[包括蛋白激酶A和C、钙/钙调蛋白依赖性蛋白激酶以及丝裂原活化蛋白激酶(MAPK)],这些信号通路通过翻译后和转录机制介导神经性疼痛的诱导和维持。特别是,外周神经损伤会导致脊髓中的小胶质细胞或星形胶质细胞或两者中的MAPK(p38、细胞外信号调节激酶和c-Jun氨基末端激酶)激活,从而导致产生使背角神经元敏感的炎症介质。背角神经元的活动反过来又会增强脊髓胶质细胞的激活。这种神经元-胶质细胞相互作用涉及正反馈机制,即使在没有持续的外周外部刺激或损伤的情况下,也可能会增强和延长神经性疼痛。本综述的目的是提供这些细胞类型中信号级联的证据,这不仅将加深我们对神经性疼痛发生机制的理解,还可能有助于确定新的药物干预靶点。