DIABETES INDUCED ALTERATION IN MET ENKEPHALIN SYNTHESIS

糖尿病引起甲硫氨酸脑啡肽合成的改变

• 批准号: 6271571
• 负责人: MALAK G KOLTA
• 金额: $ 12.33万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6271571
• 关键词: adrenal medulla; analgesia; blood glucose; brain metabolism; diabetes mellitus; diabetes mellitus therapy; dopamine; drug metabolism; enkephalins; high performance liquid chromatography; insulin; laboratory rat; medical complication; neurochemistry; opioid receptor; pain threshold; pharmacokinetics; radioimmunoassay; receptor binding; sensory mechanism; spinal cord

Diabetes Mellitus (DM) is a chronic systemic disease affecting about 5-6% of the U.S. population between the ages of 25-64. Complications of DM are numerous and affect almost every organ of the body, resulting in diverse pathological conditions including abnormal response to painful stimuli. The role of endogenous opioid peptide, metenkephalin (ME), in the mediation of the analgesic response in various experimental animal models has been documented. Studies from our laboratory have shown that streptozotocin (STZ)-induced diabetes in male rats resulted in a gradual increase in the analgesic threshold, reached a maximum at week 6-8, and remained elevated for up to 14 weeks of diabetes. This analgesic response was associated with an increase in the concentration of free ME in certain brain regions and the spinal cord. Chronic insulin replacement therapy initiated after the development of hypalgesia normalized not only glucose levels, body weight and the analgesic response in diabetic rats, but also the endogenous ME levels in the brain regions studied. The object of the present proposal is to test the hypothesis that the hypalgesia and the elevated levels of ME observed in diabetic rats are resulted from enhanced synthesis of ME coupled with a decrease in its turnover rate in various brain regions, spinal cord and adrenal medulla after the induction of diabetes. In the present investigation, we will determine; 1) the time-course of the changes in ME level by measuring PreproME mRNA, Cryptic and free, ME and its metabolite (Tyr-Gly-Gly); 2) at what time point the initiation of insulin therapy after the induction of diabetes will normalize the changes in ME activity; and 3) whether changes in ME activity results in up or down regulation of the delta-opioid receptors in the same brain regions and tissues. In addition, diabetics, diabetics + insulin and control animals will be tested for the changes in their analgesic threshold every two weeks to correlate this response with changes in the ME levels. The results of these studies should provide more focused information of the effect of diabetes on ME levels, as well as the analgesic response mediated by this opioid peptide in this systemic disease.

糖尿病 (DM) 是一种慢性全身性疾病，影响约 5-6% 的人 25-64 岁之间的美国人口。 DM 的并发症是 数量众多，几乎影响身体的每一个器官，导致不同的 病理状况，包括对疼痛刺激的异常反应。 内源性阿片肽甲氧啡肽 (ME) 在介导中的作用 各种实验动物模型的镇痛反应 记录在案。 我们实验室的研究表明，链脲佐菌素 (STZ) 诱发的雄性大鼠糖尿病导致 镇痛阈值，在第 6-8 周达到最大值，并保持较高水平 长达 14 周的糖尿病。 这种镇痛反应与 随着某些大脑区域游离 ME 浓度的增加 和脊髓。 慢性胰岛素替代治疗开始后 痛觉的发展不仅使血糖水平正常化，而且使身体正常化 糖尿病大鼠的体重和镇痛反应，以及内源性 研究的大脑区域的 ME 水平。 本提案的目的 是为了检验以下假设：痛觉减退和 ME 水平升高 在糖尿病大鼠中观察到的结果是 ME 合成增强的结果 再加上各个大脑区域的周转率下降， 诱发糖尿病后的脊髓和肾上腺髓质。 在 目前的调查，我们将确定； 1）时间进程 通过测量 PreproME mRNA、隐性和游离、ME 和 其代谢物（Tyr-Gly-Gly）； 2）什么时间点开始 诱发糖尿病后的胰岛素治疗将使这些变化正常化 在 ME 活动中； 3) ME 活动的变化是否会导致上升或下降 同一脑区 δ-阿片受体的调节 组织。 此外，糖尿病患者、糖尿病患者+胰岛素和对照动物将被 每两周测试一次镇痛阈值的变化，以 将这种反应与 ME 水平的变化联系起来。 结果 这些研究应该提供更有针对性的信息 糖尿病对 ME 水平的影响，以及由此介导的镇痛反应 阿片肽在这种全身性疾病中的作用。