Laboratory of Biopathology and Molecular Biology, University of Uberaba, Uberaba, Brazil.
Neuroscience. 2009 Nov 10;163(4):1211-9. doi: 10.1016/j.neuroscience.2009.07.052. Epub 2009 Jul 30.
This study assessed the effect of the agonist 15d-PGJ(2) administered into the rat temporomandibular joint (TMJ) on nociceptive behavioral and the anti-inflammatory potential of this prostaglandin on TMJ. It was observed that 15-deoxy-(Delta12,14)-prostaglandin J(2) (15d-PGJ(2)) significantly reduced formalin-induced nociceptive behavior in a dose dependent manner, however injection of 15d-PGJ(2) into the contralateral TMJ failed to reduce such effects. This antinociceptive effect is dependent on peroxisome proliferator-activated receptors-gamma (PPAR-gamma) since pre-treatment with GW9662 (PPAR-gamma receptor antagonist) blocked the antinociceptive effect of 15d-PGJ(2) in the TMJ. In addition, the antinociceptive effect of 15d-PGJ(2) was also blocked by naloxone suggesting the involvement of peripheral opioids in the process. Confirming this hypothesis pre-treatment with kappa, delta, but not mu receptor antagonists significantly reduced the antinociceptive effect of 15d-PGJ(2) in the TMJ. Similarly to opioid agonists, the 15d-PGJ(2) antinociceptive action depends on the nitric oxide (NO)/guanilate cyclase (cGMP)/ATP-sensitive potassium channel blocker(K(+)(ATP)) channel pathway since it was prevented by the pre-treatment with the inhibitors of nitric oxide synthase (NOS; aminoguanidine), cGMP (ODQ), or the K(+)(ATP) (glibenclamide). In addition, 15d-PGJ(2) (100 ng/TMJ) inhibits 5-HT-induced TMJ hypernociception. Besides, TMJ treated with 15d-PGJ(2) showed lower vascular permeability, assessed by Evan's Blue extravasation, and also lower neutrophil migration induced by carrageenan administration. Taken together, these results demonstrate that 15d-PGJ(2) has a potential peripheral antinociceptive and anti-inflammatory effect in the TMJ via PPAR-gamma activation. The results also suggest that 15d-PGJ(2) induced-peripheral antinociceptive response in the TMJ is mediated by kappa/delta opioid receptors by the activation of the intracellular l-arginine/NO/cGMP/K(+)(ATP) channel pathway. The pharmacological properties of the peripheral administration of 15d-PGJ(2) highlight the potential use of this PPAR-gamma agonist on TMJ inflammatory pain conditions.
本研究评估了激动剂 15d-PGJ（2）在大鼠颞下颌关节（TMJ）中的给药对疼痛行为的影响，以及这种前列腺素对 TMJ 的抗炎潜力。结果表明，15-脱氧-（Delta12,14）-前列腺素 J（2）（15d-PGJ（2））以剂量依赖的方式显著减轻福尔马林诱导的疼痛行为，但将 15d-PGJ（2）注射到对侧 TMJ 中并不能减轻这种作用。这种镇痛作用依赖于过氧化物酶体增殖物激活受体-γ（PPAR-γ），因为 GW9662（PPAR-γ 受体拮抗剂）预处理阻断了 15d-PGJ（2）在 TMJ 中的镇痛作用。此外，纳洛酮预处理也阻断了 15d-PGJ（2）的镇痛作用，表明外周阿片类物质参与了这一过程。为了证实这一假说，κ、δ受体拮抗剂预处理显著降低了 15d-PGJ（2）在 TMJ 中的镇痛作用，但 μ 受体拮抗剂预处理则没有。与阿片类激动剂类似，15d-PGJ（2）的镇痛作用依赖于一氧化氮（NO）/鸟苷酸环化酶（cGMP）/三磷酸腺苷敏感钾通道阻滞剂（K（+）（ATP））通道途径，因为它可以被一氧化氮合酶（NOS；氨基胍）抑制剂、cGMP（ODQ）或 K（+）（ATP）（格列本脲）的预处理所阻止。此外，15d-PGJ（2）（100ng/TMJ）抑制 5-HT 诱导的 TMJ 超敏反应。此外，用 15d-PGJ（2）处理的 TMJ 显示出较低的血管通透性，通过 Evan's Blue 渗出评估，并且用卡拉胶处理后也显示出较低的中性粒细胞迁移。综上所述，这些结果表明，15d-PGJ（2）通过激活 PPAR-γ，在 TMJ 中具有潜在的外周镇痛和抗炎作用。结果还表明，15d-PGJ（2）诱导的 TMJ 外周镇痛反应是通过κ/δ阿片受体介导的，通过激活细胞内 l-精氨酸/NO/cGMP/K（+）（ATP）通道途径。15d-PGJ（2）外周给药的药理学特性突出了这种 PPAR-γ 激动剂在 TMJ 炎症性疼痛情况下的潜在用途。
