Opioids as a new therapy for inflammatory arthritis: Immunopharmacological mechanisms

关节炎是一种慢性炎症性疾病，其特征是关节疼痛、肿胀和僵硬。事实上，69%的患者在发病的前三年表现为影像学糜烂和关节间隙狭窄，类风湿关节炎患者的5年死亡率可能与心血管或肿瘤疾病患者相似，这一点尚未得到充分认识。预防残疾和死亡是治疗的最终目标。然而，目前尚无治疗方法。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，类风湿关节炎患者需要在疾病早期，在糜烂和畸形发展之前进行更积极的治疗。我的工作首次表明，阿片类药物通过外周的kappa (k)受体起作用，能够改善大鼠佐剂性关节炎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有显著的有益作用。目前的建议旨在建立在大鼠获得的基本信息到阿片类药物作用的抗炎机制。现在我将运用我的专业知识将这项动物研究扩展到人体组织。我能够结合多种技术对关节炎患者的人体滑膜进行系统严谨的研究。这项工作的目的是找出为什么阿片类药物具有抗关节炎的作用，并可能潜在地导致有效的、毒性更小、成本更低的关节炎新疗法，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.