BACKGROUND: Rho-kinases (ROCKs), a family of small GTP-dependent enzymes, are involved in a range of pain models, and their inhibition typically leads to antinociceptive effects.OBJECTIVES: To study the effects of inhibiting ROCKs using two known inhibitors, Y27632 and HA1077 (fasudil), administered locally, on nociception and paw edema in rats.METHODS: A range of doses of Y27632 or HA1077 (2.5 μg to 1000 μg) were injected locally into rat paws alone or in combination with carrageenan, a known proinflammatory stimulus. Nociceptive responses to mechanical stimuli and increased paw volume, reflecting edema formation, were measured at 2 h and 3 h, using a Randall-Selitto apparatus and a hydroplethysmometer, respectively.RESULTS: Animals treated with either ROCK inhibitor showed biphasic nociceptive effects, with lower doses being associated with pronociceptive, and higher doses with antinociceptive responses. In contrast, a monophasic dose-dependent increase in edema was observed in the same animals. Local injection of 8-bromo-cyclic (c)GMP, an activator of the nitric oxide/cGMP/protein kinase G pathway, also produced biphasic effects on nociceptive responses in rat paws; however, low doses were antinociceptive and high doses were pronociceptive. Local administration of cytochalasin B, an inhibitor of actin polymerization and a downstream mediator of ROCK activity, reversed the antinociceptive effect of Y27632.CONCLUSIONS: The results of the present study suggest that ROCKs participate in the local mechanisms associated with nociception/antinociception and inflammation, with a possible involvement of the nitric oxide/cGMP/protein kinase G pathway. Also, drug effects following local administration may differ markedly from the effects following systemic administration. Finally, separate treatment of pain and edema may be needed to maximize clinical benefit in inflammatory pain.

中文翻译：

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Rho激酶抑制剂对炎性疼痛大鼠模型的双重作用

背景：Rho激酶（ROCK）是一种由GTP依赖性的小酶家族，参与多种疼痛模型，它们的抑制作用通常会产生镇痛作用。目的：使用两种已知的抑制剂研究抑制ROCKs的作用， Y27632和HA1077（法舒地尔），在大鼠疼痛和足爪水肿时局部给药方法：将一定剂量的Y27632或HA1077（2.5μg至1000μg）局部注射到大鼠爪中，单独或与角叉菜胶联合使用促炎刺激。分别使用Randall-Selitto仪器和吸水体积描记器分别在2小时和3小时测量了对机械刺激的伤害感受和增加的爪体积，反映了水肿的形成。较低的剂量与伤害感受有关，较高的剂量与感受伤害反应有关。相反，在相同的动物中观察到水肿的单相剂量依赖性增加。一氧化氮/ cGMP /蛋白激酶G通路的激活剂8-溴环（c）GMP的局部注射也对大鼠爪的伤害感受产生了双相效应。然而，低剂量具有抗伤害感受性，高剂量具有伤害感受性。局部施用细胞松弛素B（肌动蛋白聚合的抑制剂和ROCK活性的下游介质）可以逆转Y27632的抗伤害感受作用。结论：本研究结果表明，ROCKs参与了与伤害感受/伤害感受和炎症相关的局部机制，一氧化氮/ cGMP /蛋白激酶G途径可能参与其中。同样，局部给药后的药物作用可能与全身给药后的药物作用明显不同。最后，可能需要对疼痛和水肿进行单独治疗，以使炎症性疼痛的临床获益最大化。