Verri Waldiceu A, Cunha Thiago M, Parada Carlos A, Poole Stephen, Cunha Fernando Q, Ferreira Sérgio H
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto University of São Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, SP, Brazil.
Pharmacol Ther. 2006 Oct;112(1):116-38. doi: 10.1016/j.pharmthera.2006.04.001. Epub 2006 May 30.
Pain is one of the classical signs of the inflammatory process in which sensitization of the nociceptors is the common denominator. This sensitization causes hyperalgesia or allodynia in humans, phenomena that involve pain perception (emotional component+nociceptive sensation). As this review focuses mainly on animal models, which don't allow discrimination of the emotional component, the terms nociception and hypernociception are used to describe overt behavior induced by mechanical stimulation and increase of nociceptor sensitivity, respectively. Pro- and anti-inflammatory cytokines and chemokines are endogenous small protein mediators released by local or migrating cells whose balance modulates the intensity of inflammatory response. The inflammatory stimuli or tissue injuries stimulate the release of characteristic cytokine cascades, which ultimately trigger the release of final mediators responsible for inflammatory pain. These final mediators, such as prostanoids or sympathetic amines, act directly on the nociceptors to cause hypernociception, which results from the lowering of threshold due to modulation of specific voltage-dependent sodium channels. Furthermore, a direct effect of cytokines on nociceptors is also described. On the other hand, there are also anti-inflammatory cytokines, such as interleukin (IL)-10, IL-4 and IL-13, and IL-1 receptor antagonists (IL-1ra), which inhibit the production of hypernociceptive cytokines and/or the final hypernociceptive mediators, preventing the installation of or the increase in the hypernociception. This review highlights the importance of the direct and indirect actions of cytokines and chemokines in inflammatory and neuropathic hypernociception, emphasizing the evidence suggesting these molecules are potential targets to develop novel drugs and therapies for the treatment of pain.
疼痛是炎症过程的经典体征之一，其中伤害感受器的敏化是共同特征。这种敏化在人类中会导致痛觉过敏或异常性疼痛，这些现象涉及疼痛感知（情感成分+伤害性感觉）。由于本综述主要关注动物模型，而动物模型无法区分情感成分，因此使用术语伤害感受和痛觉过敏分别来描述由机械刺激引起的明显行为和伤害感受器敏感性的增加。促炎和抗炎细胞因子及趋化因子是由局部或迁移细胞释放的内源性小蛋白介质，其平衡调节炎症反应的强度。炎症刺激或组织损伤刺激特征性细胞因子级联反应的释放，最终触发负责炎症性疼痛的终末介质的释放。这些终末介质，如前列腺素或交感胺，直接作用于伤害感受器以引起痛觉过敏，这是由于特定电压依赖性钠通道的调节导致阈值降低所致。此外，还描述了细胞因子对伤害感受器的直接作用。另一方面，也存在抗炎细胞因子，如白细胞介素（IL）-10、IL-4和IL-13，以及IL-1受体拮抗剂（IL-1ra），它们抑制痛觉过敏细胞因子和/或终末痛觉过敏介质的产生，防止痛觉过敏的发生或加重。本综述强调了细胞因子和趋化因子在炎症性和神经性痛觉过敏中的直接和间接作用的重要性，强调了这些分子是开发新型药物和疼痛治疗疗法的潜在靶点的证据。
