DIABETES INDUCED ALTERATION IN MET ENKEPHALIN SYNTHESIS

糖尿病（DM）是一种慢性全身性疾病， 美国25 - 64岁的人口。 DM的并发症有 数量众多，几乎影响身体的每一个器官，导致各种各样的 病理状态，包括对疼痛刺激的异常反应。 内源性阿片肽甲啡肽（ME）在介导 在各种实验动物模型中， 记录在案。 我们实验室的研究表明链脲佐菌素 （STZ）诱导的糖尿病雄性大鼠中， 镇痛阈值在第6 - 8周达到最大值，并保持升高 长达14周的糖尿病。 这种镇痛反应与 随着某些脑区游离ME浓度的增加 和脊髓。 在以下情况下开始长期胰岛素替代治疗 痛觉减退的发展不仅使葡萄糖水平正常化， 糖尿病大鼠的体重和镇痛反应，而且内源性 研究大脑区域的ME水平。 本提案的目的 是为了验证痛觉减退和ME水平升高 在糖尿病大鼠中观察到的糖尿病大鼠的代谢产物的增加是由于ME的合成增加所致 再加上它在不同脑区的周转率下降， 脊髓和肾上腺髓质。 在 目前的调查，我们将确定; 1）的时间过程中， 通过测量PreproME mRNA、隐藏和游离、ME和 其代谢产物（Tyr-Gly-Gly）; 2）在什么时间点开始 诱导糖尿病后的胰岛素治疗将使这些变化正常化 在ME活动;和3）在ME活动的变化是否导致向上或向下 调节相同脑区的δ-阿片受体， 组织中 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镇痛阈值的变化， 将这种反应与ME水平的变化相关联。 的结果 这些研究应该提供更集中的信息， 糖尿病对ME水平的影响，以及由此介导的镇痛反应 阿片肽在这种系统性疾病中的作用。

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.