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长期作用 耐受依赖和禁欲过程。在本提案中， 根据该实验室的研究，将提出以下假设 验证：（a）神经肽如Pro-Leu-Gly-NH 2和类似物抑制 作用于中枢神经系统的吗啡耐受-依赖 (CNS)、（B）多巴胺（DA）和特定区域的多种阿片受体 参与吗啡耐受-依赖和戒断 过程和（c）肽如Pro-Leu-Gly-NH 2（MIF）和环（Leu-Gly） (CLG)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中进行， 大鼠，以确定这是一种普遍现象还是种属依赖性。的 通过皮下注射使动物对吗啡耐受和依赖， 植入吗啡丸将评估耐受程度 通过测量对变化的反应（例如镇痛和体温过低）， 吗啡和安慰剂颗粒植入啮齿动物中的吗啡剂量。的 身体依赖程度将通过确定强度来评估 的症状，如体温过低，刻板的跳跃和体重减轻， 吗啡的戒断肽对发育的影响 对吗啡的耐受和依赖以及吗啡的症状 禁欲将被确定。多巴胺受体配体3 H-SCH的结合 23390和3 H-多潘立酮（分别为D1和D2受体）以及阿片类药物 受体配体，3 H-DAMGO（mu），3 H-DPDPE（delta）和3 H-U 69593（k）， CNS区域（脊髓、杏仁核、海马、下丘脑、体 纹状体、脑桥和髓质、中脑和大脑皮质）将被 测定初步研究表明，在耐受性依赖和 戒断过程DA和阿片受体的影响差异， CNS区域。因此，将在中枢神经系统各区域开展研究 为了确定中枢神经系统中DA和阿片类物质的变化， 受体是通过阿片机制介导的，纳洛酮对 这些变化将被确定。一旦多巴胺和鸦片的特异性 受体的变化，然后第二信使的参与， 系统（腺苷酸环化酶和磷酸肌醇）将被确定。效果 对吗啡耐受性的影响 依赖性将决定建立中枢或外周机制 的行动。为了验证缩氨酸抑制吗啡耐受的假设 通过修饰DA和阿片受体，它们对吗啡诱导的 将确定中枢神经系统特定区域的变化。这些研究 不仅能让我们更好地了解鸦片制剂的作用机制 成瘾的过程，而且还开发更安全的药物， 阿片类药物成瘾和痛苦的戒断综合征的管理。

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.