DIABETES INDUCED ALTERATION IN MET ENKEPHALIN SYNTHESIS

糖尿病(DM)是一种慢性系统性疾病，约有5%-6%的人患有糖尿病 25岁之间的美国人口--。糖尿病的并发症有 数量众多，几乎影响到身体的每个器官，导致不同的 病理状态，包括对疼痛刺激的异常反应。 内源性阿片肽甲脑啡肽(ME)在中介中的作用 在各种实验动物模型中的止痛反应的研究 有记录在案。我们实验室的研究表明，链脲佐菌素 链脲佐菌素(STZ)诱导的雄性大鼠糖尿病后， 止痛阈值，在6-8周达到最大值，并保持在较高水平 治疗长达14周的糖尿病。这种止痛反应与 随着某些脑区中游离ME浓度的增加 和脊髓。术后开始慢性胰岛素替代治疗 痛觉减退的发展不仅使血糖水平正常化，还使身体 糖尿病大鼠的体重和镇痛反应，也是内源性的 被研究的大脑区域中的ME水平。本提案的目的是 是为了测试痛觉减退和ME水平升高的假设 在糖尿病大鼠中观察到的是ME合成增强的结果 再加上它在大脑各个区域的周转率下降， 糖尿病诱导后脊髓和肾上腺髓质。在 目前的调查，我们将确定；1)时间进程 测定隐匿型和游离型前ProME、ME和 其代谢物(酪氨酸-甘氨酸-甘氨酸)；2)在什么时间点开始 糖尿病诱导后的胰岛素治疗将使这种变化正常化。 ME活性的变化；以及3)ME活性的变化是否导致上升或下降 在相同的脑区和脑内的增量-阿片受体的调节 纸巾。 此外，糖尿病患者、糖尿病患者+胰岛素和对照动物将 每两周测试一次他们的止痛阈值的变化 将这种反应与代谢能水平的变化联系起来。结果是 这些研究应该提供更有针对性的信息，了解 糖尿病对ME水平的影响及其介导的止痛反应 阿片肽在这种全身性疾病中的作用。

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.