Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Avenida Bandeirantes, 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2013 Jan;386(1):51-9. doi: 10.1007/s00210-012-0813-4. Epub 2012 Nov 28.
Platelet-activating factor (PAF) and its receptor (PAFR) have been shown to be involved in several inflammatory events, including neutrophil chemoattraction and nociception. The present study addressed the role of PAF in the genesis of articular hyperalgesia in a model of joint inflammation. Zymosan-induced articular hyperalgesia, oedema and neutrophil migration were dose-dependently reduced following pretreatment with selective PAFR antagonists, UK74505 (5, 10 and 20 mg/kg) and PCA4248 (3, 10, 30 mg/kg). These parameters were also reduced in PAF receptor-deficient mice (PAFR(-/-)). The hyperalgesic action of PAF was further confirmed by the demonstration that joint injection of PAF induces a dose- (0.3, 1 and 3 μg/joint), time- and PAFR-dependent articular hyperalgesia and oedema. The PAF hyperalgesic mechanisms were dependent on prostaglandins, leukotrienes and neutrophils, as PAF-induced articular hyperalgesia was inhibited by indomethacin (COX inhibitor), MK886 (leukotrienes synthesis inhibitor) or fucoidan (leukocyte rolling inhibitor). Furthermore, PAF-induced hyperalgesia was reduced in 5-lypoxigenase-null mice. In corroboration of these findings, intra-articular injection of PAF promotes the production of LTB(4) as well as the recruitment of neutrophils to the joint. These results suggest that PAF may participate in the cascade of events involved in the genesis of articular inflammatory hyperalgesia via stimulation of prostaglandins, leukotrienes and neutrophil migration. Finally, targeting PAF action (e.g., with a PAFR antagonist) might provide a useful therapeutic approach to inhibit articular inflammatory hyperalgesia.
血小板激活因子（PAF）及其受体（PAFR）已被证明参与了几种炎症事件，包括中性粒细胞趋化和痛觉过敏。本研究探讨了 PAF 在关节炎症模型中关节痛觉过敏发生中的作用。在选择性 PAFR 拮抗剂 UK74505（5、10 和 20mg/kg）和 PCA4248（3、10 和 30mg/kg）预处理后，佐剂型关节炎诱导的关节痛觉过敏、水肿和中性粒细胞迁移呈剂量依赖性降低。在 PAF 受体缺陷型小鼠（PAFR(-/-)）中，这些参数也降低。PAF 引起的关节痛觉过敏作用进一步通过以下事实得到证实：关节内注射 PAF 可诱导剂量依赖性（0.3、1 和 3μg/关节）、时间依赖性和 PAFR 依赖性关节痛觉过敏和水肿。PAF 的痛觉过敏机制依赖于前列腺素、白三烯和中性粒细胞，因为 PAF 诱导的关节痛觉过敏被吲哚美辛（COX 抑制剂）、MK886（白三烯合成抑制剂）或褐藻聚糖（白细胞滚动抑制剂）抑制。此外，5-脂氧合酶缺陷型小鼠中 PAF 诱导的痛觉过敏减少。这些发现的佐证是，关节内注射 PAF 可促进 LTB4 的产生以及中性粒细胞向关节的募集。这些结果表明，PAF 可能通过刺激前列腺素、白三烯和中性粒细胞迁移，参与关节炎症性痛觉过敏发生的级联反应。最后，靶向 PAF 作用（例如，使用 PAFR 拮抗剂）可能为抑制关节炎症性痛觉过敏提供一种有用的治疗方法。
