Department of Internal Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil.
Br J Pharmacol. 2011 Sep;164(2b):828-35. doi: 10.1111/j.1476-5381.2011.01469.x.
We investigated the effect of the phosphodiesterase-5 inhibitor, tadalafil, on the acute hypernociception in rat models of arthritis.
Rats were treated with either an intra-articular injection of zymosan (1 mg) or surgical transection of the anterior cruciate ligament (as an osteoarthritis model). Controls received saline intra-articular or sham operation respectively. Joint pain was evaluated using the articular incapacitation test measured over 6 h following zymosan or between 4 and 7 days after anterior cruciate ligament transection. Cell counts, tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), and the chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1) were measured in joint exudates 6 h after zymosan. Groups received tadalafil (0.02-0.5 mg·kg⁻¹ per os) or saline 2 h after intra-articular zymosan. Other groups received the µ-opioid receptor antagonist naloxone or the cGMP inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) before tadalafil.
Tadalafil dose-dependently inhibited hypernociception in zymosan and osteoarthritis models. In zymosan-induced arthritis, tadalafil significantly decreased cell influx and TNF-α release but did not alter IL-1 or CINC-1 levels. Pretreatment with ODQ but not with naloxone prevented the anti-inflammatory effects of tadalafil.
Therapeutic oral administration of tadalafil provided analgesia mediated by guanylyl cyclase and was independent of the release of endogenous opioids. This effect of tadalafil was associated with a decrease in neutrophil influx and TNF-α release in inflamed joints.
我们研究了磷酸二酯酶-5 抑制剂他达拉非对关节炎大鼠模型急性痛觉过敏的影响。
大鼠接受关节内注射酵母聚糖（1mg）或前交叉韧带切断术（作为骨关节炎模型）。对照组分别接受关节内注射生理盐水或假手术。在酵母聚糖注射后 6 小时或前交叉韧带切断后 4 至 7 天，使用关节失能试验评估关节疼痛。在酵母聚糖注射后 6 小时测量关节渗出液中的细胞计数、肿瘤坏死因子-α（TNF-α）、白细胞介素-1（IL-1）和趋化因子细胞因子诱导的中性粒细胞趋化因子-1（CINC-1）。各组在关节内注射酵母聚糖后 2 小时给予他达拉非（0.02-0.5mg·kg⁻¹ 口服）或生理盐水。其他组在给予他达拉非之前给予µ-阿片受体拮抗剂纳洛酮或环鸟苷酸抑制剂 1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮（ODQ）。
他达拉非剂量依赖性地抑制酵母聚糖和骨关节炎模型中的痛觉过敏。在酵母聚糖诱导的关节炎中，他达拉非显著减少细胞浸润和 TNF-α释放，但不改变 IL-1 或 CINC-1 水平。ODQ 预处理而不是纳洛酮预处理可预防他达拉非的抗炎作用。
口服给予他达拉非可提供由鸟苷酸环化酶介导的镇痛作用，且与内源性阿片类物质的释放无关。他达拉非的这种作用与炎症关节中中性粒细胞浸润和 TNF-α释放减少有关。
