Pharmacodynamics Unit, Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.
Physiol Rev. 2012 Oct;92(4):1699-775. doi: 10.1152/physrev.00048.2010.
Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechanical, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs.
外周介质可以通过两种机制促进炎症性和神经性疼痛及其伴随症状（痛觉过敏和感觉异常）的发展和维持。这些物质对伤害性神经末梢或纤维的激活或兴奋导致动作电位的产生，然后这些动作电位传递到中枢神经系统，并可能引起疼痛感觉。伤害感受器的敏化是指它们对热、机械或化学刺激的反应性增加，这可能转化为相应的痛觉过敏。本综述旨在阐述包括缓激肽、前列腺素、血栓素、白三烯、血小板激活因子和一氧化氮在内的炎症介质对伤害性初级传入神经元的兴奋和敏化作用。详细讨论了这些介质作用的表现、受体分子和细胞内信号转导机制。关于信号转导，大多数报道的数据都是从转染的非神经元细胞和培养感觉神经元的胞体中获得的，因为这些结构更容易直接研究感觉和信号转导。与细胞模型相比，感觉神经元的外周过程在生物物理学、超微结构和受体及离子通道的装备方面与疼痛刺激实际上在体内影响伤害感受器的过程有明显的不同。因此，我们努力强调信号转导机制，这些机制的支持数据来自分子、细胞和行为模型，与反映外周伤害性神经末梢特性的发现一致。这些信号通路的鉴定分子元件可以作为开发新型镇痛药物的有效靶点。
