Opioids as a new therapy for inflammatory arthritis: Immunopharmacological mechanisms

关节炎是一种慢性炎症性疾病，以关节疼痛、肿胀和僵硬为特征。事实上，69%的患者在疾病的头三年中出现了放射学侵蚀和关节间隙狭窄，而人们对类风湿性关节炎患者的5年死亡率可能与心血管疾病或肿瘤患者相似的认识不够。预防残疾和死亡是治疗的最终目标。然而，目前还没有治愈方法。相反，目前的治疗旨在缓解症状和改善功能表现。现在越来越多的人认识到，类风湿性关节炎患者需要在疾病早期、在侵蚀和畸形发展之前进行更积极的治疗。我的工作首次表明，通过外周kappa(K)受体作用的阿片类药物能够改善大鼠佐剂性关节炎的疾病症状的发生率和严重程度。组织学和放射学分析显示对关节病理学有显著的有益影响。本提案试图将在大鼠身上获得的这一基本信息建立在阿片类药物作用的抗炎机制上。现在，我将运用我的专业知识，将这项动物研究扩展到人类组织。我能够结合多种技术对关节炎患者的人类滑膜进行系统和严格的研究。这项工作旨在找出为什么阿片类药物具有抗关节炎的作用，并可能导致有效、低毒和廉价的关节炎新疗法，并增加我们对关节炎发病机制的理解。

Arthritis is a chronic inflammatory disorder characterized by joint pain, swelling and stiffness. In fact, 69% of patients present with radiographic erosions and joint space narrowing during the first three years of the disease and it is insufficiently appreciated that patients with rheumatoid arthritis may have a 5-year mortality similar to patients with cardiovascular or neoplastic disease. Prevention of disability and death is the ultimate goal of treatment. However, no cure is yet available. Instead, current treatment is aimed at relieving symptoms and improving functional performance. There is now a growing recognition that patients with rheumatoid arthritis require more agressive treatment early in the disease, before the development of erosions and deformity. My work has shown for the first time that opioid drugs that act via kappa (k) receptors in the periphery are able to ameliorate the incidence and severity of disease symptoms in rat adjuvant arthritis. Histological and radiological analysis reveals a significant, beneficial effect on joint pathology. The present proposal seeks to build upon this basic information gained in rats into the anti-inflammatory mechanisms of opioid action. I will now apply my expertise to extend this research in animals to human tissues. I am able to combine multiple techniques to carry out a systematic and rigorous study on human synovium from arthritis patients. This work aims to find out why opioids have anti-arthritic actions and might potentially lead to potent, less toxic and less expensive new therapies for arthritis and increase our understanding of the pathogenesis of arthritis.