Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, UNICAMP, Rua Monteiro Lobato, 255, Campinas, SP, CEP 13083-862, Brazil.
Inflamm Res. 2018 Apr;67(4):301-314. doi: 10.1007/s00011-017-1122-7. Epub 2017 Dec 19.
We investigated whether: (1) P2 × 7 receptor activation by its agonist (BzATP) induces articular hyperalgesia in the rat's knee joint via inflammatory mechanisms and (2) activation of P2 × 7 receptors by endogenous ATP contributes to the articular hyperalgesia induced by bradykinin, TNF-α, IL-1β, CINC-1, PGE and dopamine.
The articular hyperalgesia was quantified using the rat knee joint incapacitation test. The knee joint inflammation, characterized by the concentration of pro-inflammatory cytokines and by neutrophil migration, was quantified in the synovial lavage fluid by ELISA and myeloperoxidase enzyme activity assay, respectively.
BzATP induced a dose-dependent articular hyperalgesia in the rat's knee joint that was significantly reduced by the selective antagonists for P2 × 7, bradykinin B or B receptors, β or β adrenoceptors, and by pre-treatment with Indomethacin. BzATP induced a local increase of TNF-α, IL-1β, IL-6, and CINC-1 concentration and neutrophil migration into the knee joint. The co-administration of the selective P2 × 7 receptor antagonist A-740003 significantly reduced the articular hyperalgesia induced by bradykinin and dopamine, but not by TNF-α, IL-1β, CINC-1, and PGE.
P2 × 7 receptor activation induces articular hyperalgesia mediated by the previous inflammatory mediator release. P2 × 7 receptor-induced articular hyperalgesia is sustained by the involvement of this purinergic receptor in bradykinin and dopamine-induced hyperalgesia in the knee joint.
我们研究了以下两个问题：（1）其激动剂（BzATP）对 P2×7 受体的激活是否通过炎症机制引起大鼠膝关节关节痛觉过敏；（2）内源性 ATP 对 P2×7 受体的激活是否有助于缓激肽、TNF-α、IL-1β、CINC-1、PGE 和多巴胺引起的关节痛觉过敏。
采用大鼠膝关节失能试验来量化关节痛觉过敏。通过 ELISA 和髓过氧化物酶酶活性测定法分别在滑膜灌流液中对炎症因子浓度和中性粒细胞迁移进行量化，以确定关节炎症。
BzATP 诱导大鼠膝关节产生剂量依赖性的关节痛觉过敏，这种痛觉过敏可被 P2×7、缓激肽 B 或 B 受体、β 或β肾上腺素受体的选择性拮抗剂以及吲哚美辛预处理显著减轻。BzATP 诱导 TNF-α、IL-1β、IL-6 和 CINC-1 浓度增加，并引起中性粒细胞向膝关节迁移。选择性 P2×7 受体拮抗剂 A-740003 的共同给药显著减轻了缓激肽和多巴胺引起的关节痛觉过敏，但对 TNF-α、IL-1β、CINC-1 和 PGE 引起的关节痛觉过敏没有影响。
P2×7 受体的激活诱导了先前炎症介质释放介导的关节痛觉过敏。P2×7 受体诱导的关节痛觉过敏是通过该嘌呤能受体参与缓激肽和多巴胺引起的膝关节痛觉过敏来维持的。
