OPIOID AND NONOPIOID ACTIONS OF DYNORPHIN IN PAIN

强啡肽在疼痛中的阿片类和非阿片类药物作用

• 批准号: 6150451
• 负责人: Frank Porreca
• 金额: $ 22.55万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150451
• 关键词: NMDA receptors; antiserum; cellular pathology; dynorphins; high performance liquid chromatography; hyperalgesia; immunologic assay /test; laboratory rat; nerve injury; neurochemistry; neurons; neuropharmacology; pain; receptor binding; spinal cord; spinal cord surgery; tissue /cell culture; transfection

DESCRIPTION (Applicant's Abstract) One of the most significant health problems in our country relates directly to the consequences of pain. Estimates suggest that as many as 30 million Americans suffer from chronic pain which is resistant to medical treatment. One of the chronic abnormal pain states which is extremely difficult to treat is commonly referred to as "neuropathic pain." Our understanding of this condition is limited, but has been increased in recent years by development of animal models in which injuries are made to peripheral nerves to produce signs which reflect some aspects of human neuropathic pain states. A striking result of these injuries is a substantial increase in the expression of spinal dynorphin. It is known that dynorphin may rapidly be degraded to des-Tyr fragments which do not interact with opioid receptors and that dynorphin can produce a significant number of effects which are non-opioid in nature. This proposal is aimed at testing the hypothesis that the spinal dynorphin is intimately involved in either the initiation or maintenance of nerve-injury related pain through non-opioid mechanisms. This hypothesis will be systematically tested by (a) measurement of whether and when dynorphin expression occurs in the spinal cord following specific nerve injuries; (b) determination of the functional consequences of spinal dynorphin and its role in maintenance of the post-injury state; (c)determination of the consequences of preemptive inhibition of dynorphin activity to evaluate its role in initiation of the nerve-injury consequences; (d) identification of a mechanism by which dynorphin may produce such pathological actions via interaction with a novel binding site on the NMDA receptor complex; and (e) direct evaluation of the effects of dynorphin on the viability of neurons. The present studies should reveal much about the role of dynorphin in post-injury processes in the spinal cord. It is expected that treatments that prevent the expression of spinal dynorphin or that block the actions of pathological levels of dynorphin at a specific site on the NMDA receptor complex should provide additional therapeutic benefit in the treatment of neuropathic pain.

描述（申请人摘要） 我国最严重的健康问题之一直接关系到 痛苦的后果 据估计， 美国人患有慢性疼痛，这种疼痛对药物治疗有抵抗力。 一种慢性异常疼痛状态， 治疗通常被称为“神经性疼痛”。“我们对 这种情况是有限的，但近年来有所增加， 外周神经损伤动物模型的开发 以产生反映人类神经性疼痛的某些方面的迹象， states. 这些伤害的一个显著结果是， 脊髓强啡肽的表达。 已知强啡肽可以迅速 被降解为不与阿片受体相互作用的脱Tyr片段 强啡肽可以产生大量的效应， 非阿片类药物 这一提议旨在检验以下假设： 脊髓强啡肽密切参与神经元的起始或 通过非阿片类机制维持神经损伤相关疼痛。 这一假设将通过以下方式得到系统的检验：（a）衡量是否 而当强啡肽表达发生在脊髓后， 神经损伤;（B）确定脊髓损伤的功能后果 强啡肽及其在维持损伤后状态中的作用; （c）确定强啡肽的预先抑制的后果 活性，以评价其在神经损伤起始中的作用 后果;（d）确定强啡肽可能 通过与新的结合位点相互作用产生这种病理作用 对NMDA受体复合物的影响;和（e）直接评价 强啡肽对神经元活力的影响。 目前的研究应该揭示 强啡肽在脊髓损伤后过程中的作用 线. 预期阻止脊髓神经元表达的治疗是有效的。 强啡肽或阻断病理水平的强啡肽的作用， NMDA受体复合物上的特定位点应提供额外的 在治疗神经性疼痛中的治疗益处。