HYPOTHALAMUS & NARCOTIC EFFECTS

长期目标是开发具有口服活性的神经肽类似物， 抑制吗啡的酶稳定性和作用时间长 耐受依赖和禁欲过程。在本提案中， 基于本实验室的研究，将提出以下假设 证实：(A)Pro-Leu-Gly-NH2等神经肽抑制 作用于中枢神经系统的吗啡耐受依赖 中枢神经系统(CNS)、(B)多巴胺(DA)和特定区域的多种阿片受体 中枢神经系统与吗啡耐受、依赖和戒断有关 过程和(C)Pro-Leu-Gly-NH2(MIF)和环状(Leu-Gly)等肽 (CLG)通过以下方式抑制吗啡耐受依赖和戒断过程 影响多巴胺和阿片受体。研究将在小鼠和 以确定这是一种普遍现象还是与物种有关。这个 通过皮下注射使动物对吗啡产生耐受和依赖 植入吗啡药丸。将对容忍度进行评估 通过测量对不同变化的反应(如止痛和低温) 吗啡和安慰剂颗粒植入啮齿动物体内的吗啡剂量。这个 身体依赖的程度将通过测定强度来评估 体温过低、千篇一律的跳跃和体重减轻等症状 吗啡的戒断。多肽在肿瘤发生发展中的作用 对吗啡的耐受和依赖以及对吗啡症状的依赖 禁欲是有决心的。多巴胺受体配体~3H-SCH的结合 23390和3H-多潘立酮(分别为D_1和D_2受体)和阿片类药物 受体配体，3H-DAMGO(MU)，3H-DPDPE(Delta)和3H-U 69593(K)至 中枢神经系统区域(脊髓、杏仁核、海马体、下丘脑、体部 纹状体、脑桥和延髓、中脑和大脑皮层) 下定决心。初步研究表明，在耐受性依赖和 戒断过程中DA和阿片受体受到不同程度的影响 中枢神经系统区域。因此，将对中南半球的区域进行研究 为了确定中枢神经系统多巴胺和阿片类药物是否发生变化 受体是通过阿片机制介导的，纳曲酮对其影响 这样的变化将是确定的。一旦多巴胺和阿片类药物的特异性 受体变化确立后，第二信使参与其中 系统(腺苷环化酶和磷酸肌醇)将被测定。效果 脑室注射多肽对吗啡耐受性的影响-- 将确定依赖建立中央或外围机制 行动的一部分。为了验证多肽抑制吗啡耐受的假说 通过修饰多巴胺和阿片受体，它们对吗啡诱导的影响 将确定中枢神经系统特定区域的变化。这些研究 可能不仅有助于更好地理解鸦片类药物的作用机制 成瘾过程，也是更安全的药物的开发 阿片成瘾和痛苦戒断综合征的管理。

The long term goal is to develop neuropeptide analogs with oral activity, enzymatic stability and long duration of action in inhibiting morphine tolerance-dependence and abstinence processes. In the present proposal, based on the studies from this laboratory, the following hypotheses will be verified: (a) neuropeptides like Pro-Leu-Gly-NH2 and analogs inhibit morphine tolerance-dependence by acting on the central nervous system (CNS), (b) dopamine (DA) and multiple opiate receptors of specific regions of the CNS are involved in morphine tolerance-dependence and abstinence processes and (c) peptides like Pro-Leu-Gly-NH2 (MIF) and cyclo(Leu-Gly) (CLG) inhibit morphine tolerance-dependence and abstinence processes by affecting DA and opiate receptors. Studies will be carried out in mice and rats to establish if it is a general phenomena or is species dependent. The animals will be made tolerant to and dependent on morphine by subcutaneous implantation of morphine pellets. The degree of tolerance will be assessed by measuring the responses (e.g. analgesia and hypothermia) to varying doses of morphine in morphine and placebo pellet implanted rodents. The degree of physical dependence will be assessed by determining the intensity of symptoms like hypothermia, stereotyped jumping and weight loss during the withdrawal of morphine. The effect of peptides on the development of tolerance to and dependence on morphine and on the symptoms of morphine abstinence will be determined. The binding of DA receptor ligands 3 H-SCH 23390 and 3 H-domperidone (D1 and D2 receptors, respectively) and of opiate receptor ligands, 3 H-DAMGO (mu), 3 H-DPDPE (delta) and 3 H-U 69593 (k) to CNS regions (spinal cord, amygdala, hippocampus, hypothalamus, corpus striatum, pons and medulla, midbrain and cerebral cortex) will be determined. Preliminary studies show that in tolerance-dependence and abstinence processes DA and opiate receptors are affected differentially in CNS regions. Hence studies will be carried out with the regions of the CNS indicated above,.In order to establish whether CNS changes in DA and opiate receptors are mediated via opiate mechanism the effect of naltrexone on such changes will be determined. Once the specificity of DA and opiate receptor changes is established, then the involvement of second messenger systems (adenylate cyclase and phosphoinositol) will be determined. Effect of peptides given intracerebroventricularly on morphine tolerance-- dependence will be determined to establish central or peripheral mechanism of action. To test the hypothesis that peptides inhibit morphine tolerance by modifying DA and opiate receptors, their effect on morphine induced changes in specific regions of the CNS will be determined. These studies may lead not only to better understanding of the mechanisms in opiate addiction processes but also to the development of safer drugs in the management of opioid addiction and distressing withdrawal syndrome.