Antiinflammatory and analgesic effects of somatostatin released from capsaicin-sensitive sensory nerve terminals in a Freund's adjuvant-induced chronic arthritis model in the rat
Antiinflammatory and analgesic effects of somatostatin released from capsaicin-sensitive sensory nerve terminals in a Freund's adjuvant-induced chronic arthritis model in the rat
复制标题
DOI：
10.1002/art.20184
复制
发表时间：
2004-05-01
影响因子：
--
通讯作者：
Szolcsányi, J
中科院分区：
文献类型：
--
作者：
Helyes, Z;Szabó, A;Szolcsányi, J
Objective.我们以前证明，从辣椒素敏感的初级感觉神经元激活的外周末梢释放的生长抑素（SOM）抑制急性炎症和伤害感受。本研究旨在研究在弗氏完全佐剂（CFA）诱导的关节炎模型中，神经源性生长抑素在慢性炎症中的全身“感觉分泌”功能。通过将CFA皮下注射到刘易斯大鼠的左后爪和尾根中诱发胫跗关节炎。持续3周，通过体积测量法测量爪的体积，并通过感觉测量法测量机械伤害感受阈值。SOM的血浆浓度测定放射免疫法，并进行关节的组织学研究。为了损害辣椒素敏感性传入神经的功能，在CFA给药前7天皮下注射辣椒素受体（VR 1/TRPV 1）激动剂树脂毒素（RTX）（30、70和100 μ g/kg，随后3天）。SOM受体拮抗剂环生长抑素（c-SOM; 20 μ g/kg）或另一组合成七肽激动剂TT-232（2 × 50-400 μ g/kg）每天腹腔内给药。RTX预处理或c-SOM注射显着增加水肿和机械痛觉过敏的CFA处理和对侧爪。基于滑膜增厚、细胞浸润、软骨破坏和骨侵蚀的组织学评分在RTX和c-SOM注射组中也显著更高。TT-232可剂量依赖性降低这些参数。血浆SOM样免疫反应性在第21天增加了4倍，并且被RTX预处理以及TT-232每日给药抑制。我们的数据表明，SOM释放到循环中的辣椒素敏感的传入反应，长时间激活发挥全身镇痛和镇痛作用。TT-232可以为慢性关节炎的治疗开辟新的前景。
Objective. We previously demonstrated that somatostatin (SOM) released from the activated peripheral terminals of capsaicin-sensitive primary sensory neurons inhibits acute inflammation and nociception. This study was undertaken to examine this systemic "sensocrine" function of neuronally derived somatostatin in chronic inflammation in the Freund's complete adjuvant (CFA)-induced arthritis model.Methods. Arthritis of the tibiotarsal joint of Lewis rats was evoked by subcutaneous injection of CFA into the left hind paw and the tail root. For 3 weeks, the volume of the paws was measured by plethysmometry, and the mechanonociceptive thresholds were measured by esthesiometry. Plasma concentrations of SOM were determined by radioimmunoassay, and histologic studies of the joints were performed. To impair the function of capsaicin-sensitive afferents, the capsaicin receptor (VR1/TRPV1) agonist resiniferatoxin (RTX) was injected subcutaneously (30, 70, and 100 mug/kg on 3 subsequent days) 7 days before CFA administration. The SOM receptor antagonist cyclosomatostatin (c-SOM; 20 mug/kg) or, in another group, the synthetic heptapeptide agonist TT-232 (2 x 50-400 mug/kg) was administered intraperitoneally every day.Results. RTX pretreatment or c-SOM injection significantly increased edema and mechanical hyperalgesia of both CFA-treated and contralateral paws. The histologic score based on synovial thickening, cell infiltration, cartilage destruction, and bone erosion was also significantly higher both in the RTX- and the c-SOM-injected groups. These parameters were dose-dependently decreased by TT-232. Plasma SOM-like immunoreactivity increased 4-fold on the twenty-first day, and was inhibited by RTX pretreatment, as well as by daily administration of TT-232.Conclusion. Our data suggest that SOM released into the circulation from capsaicin-sensitive afferents in response to prolonged activation exerts systemic antiinflammatory and analgesic effects. TT-232 can open new perspectives in the treatment of chronic arthritis.