Kurita Maki, Yamaguchi Hiroshi, Okamoto Ken, Kotera Takashi, Oka Michiko
Research Laboratories, Nippon Shinyaku Co., Ltd., Minami-ku, Kyoto, Japan.
Prostate. 2018 Nov;78(15):1157-1165. doi: 10.1002/pros.23690. Epub 2018 Jul 15.
Experimental autoimmune prostatitis (EAP) is most often used as a nonbacterial model of chronic prostatitis/chronic pelvic pain. We investigated the development of chronic pelvic pain and inflammatory changes in rat EAP and examined the effect of a single treatment with phosphodiesterase 5 (PDE5) inhibitors on the chronic pelvic pain.
EAP was induced in rats by intradermal injection of rat prostate antigen and complete Freund's adjuvant on days 0 and 28. On day 42, after antigen injection, prostatic inflammatory changes, including the mRNA and protein levels of cytokines/chemokines, were measured and histological analysis of the prostate was performed. Pelvic pain was measured by applying von Frey filaments to the lower abdomen. To confirm that this model is appropriate for evaluating pelvic pain, we tested two drugs, celecoxib and pregabalin, which are clinically used for the treatment of prostatitis-related pain. Subsequently, we examined the effects of single treatments with three phosphodiesterase 5 inhibitors, including tadalafil, on pelvic pain in this model.
On day 42, after antigen injection, the mRNA levels of 44 of 84 kinds of cytokines/chemokines and their receptors increased significantly in EAP rats, as did the protein levels of seven of 23 kinds of cytokines/chemokines. Histological analysis revealed inflammation characterized by neutrophils and/or mononuclear cells in the glandular and stromal tissue of the ventral prostate from rats in the EAP group. Some animals in this group showed fibrosis and hemorrhage in the stromal tissue. Pelvic pain had developed in EAP rats, which was attenuated by a single treatment with celecoxib or pregabalin, suggesting that EAP is an appropriate model for prostatitis-related pain. A single treatment with any of the three PDE5 inhibitors tested attenuated the chronic pelvic pain.
Prostatitis leads to inflammatory changes in the prostate, which may contribute to the development and maintenance of chronic pelvic pain. PDE5 inhibitors, including tadalafil, may have the ability to block chronic pelvic pain.
实验性自身免疫性前列腺炎（EAP）最常被用作慢性前列腺炎/慢性盆腔疼痛的非细菌性模型。我们研究了大鼠EAP中慢性盆腔疼痛的发展和炎症变化，并检测了磷酸二酯酶5（PDE5）抑制剂单次治疗对慢性盆腔疼痛的影响。
在第0天和第28天通过皮内注射大鼠前列腺抗原和完全弗氏佐剂诱导大鼠发生EAP。在第42天，抗原注射后，测量前列腺的炎症变化，包括细胞因子/趋化因子的mRNA和蛋白质水平，并对前列腺进行组织学分析。通过将von Frey细丝施加于下腹部来测量盆腔疼痛。为了确认该模型适用于评估盆腔疼痛，我们测试了两种临床上用于治疗前列腺炎相关疼痛的药物，塞来昔布和普瑞巴林。随后，我们检测了三种PDE5抑制剂（包括他达拉非）单次治疗对该模型中盆腔疼痛的影响。
在第42天抗原注射后，EAP大鼠中84种细胞因子/趋化因子及其受体中的44种mRNA水平显著升高，23种细胞因子/趋化因子中的7种蛋白质水平也显著升高。组织学分析显示，EAP组大鼠腹侧前列腺的腺组织和基质组织中有以中性粒细胞和/或单核细胞为特征的炎症。该组中的一些动物在基质组织中出现纤维化和出血。EAP大鼠出现了盆腔疼痛，用塞来昔布或普瑞巴林单次治疗可减轻疼痛，这表明EAP是前列腺炎相关疼痛的合适模型。测试的三种PDE5抑制剂中的任何一种单次治疗均可减轻慢性盆腔疼痛。
前列腺炎导致前列腺的炎症变化，这可能有助于慢性盆腔疼痛的发生和维持。包括他达拉非在内的PDE5抑制剂可能具有阻断慢性盆腔疼痛的能力。
