OPIOID ACTIONS AND NEUROPEPTIDES

阿片类药物的作用和神经肽

• 批准号: 2115955
• 负责人: HEMENDRA N BHARGAVA
• 金额: $ 9.86万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2115955
• 关键词: analog; body weight; centrally acting drug; chemical synthesis; dopamine receptor; drug addiction; drug addiction antagonist; drug interactions; drug withdrawal; hypothermia; laboratory mouse; laboratory rat; morphine; naltrexone; neuropeptides; receptor binding; second messengers; spinal cord

This is a request for an ADAMHA Research Scientist Development Award (K02). 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 3H-SCH 23390 and 3H-domperidone (D1 and D2 receptors, respectively) and of opiate receptor ligands, 3H-DAMGO (mu), 3H-DPDPE (sigma) and 3H-U-69,593 (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 specific brain regions. 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. the effect of different degrees of tolerance induced by implanting different number of pellets during different time intervals on the above biochemical parameters will be monitored. 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.

这是 ADAMHA 研究科学家发展奖 (K02) 的请求。 长期目标是开发具有口服活性的神经肽类似物， 酶稳定性和抑制吗啡作用持续时间长 耐受依赖和节制过程。 在本提案中， 根据本实验室的研究，将提出以下假设 已验证：(a) 神经肽如 Pro-Leu-Gly-NH2 和类似物抑制 作用于中枢神经系统产生吗啡耐受依赖性 (CNS), (b) 多巴胺 (DA) 和特定区域的多种阿片受体 中枢神经系统参与吗啡耐受依赖性和戒断 过程和 (c) 肽，如 Pro-Leu-Gly-NH2 (MIF) 和环 (Leu-Gly) (CLG) 通过抑制吗啡耐受依赖性和戒断过程 影响 DA 和阿片受体。 研究将在老鼠身上进行 大鼠以确定它是否是普遍现象或取决于物种。 通过以下方式使动物对吗啡产生耐受和依赖 皮下植入吗啡颗粒。 耐受程度 将通过测量反应来评估（例如镇痛和 体温过低）到吗啡和安慰剂颗粒中不同剂量的吗啡 植入的啮齿动物。 身体依赖性的程度将通过以下方式评估 确定症状的强度，如体温过低、刻板跳跃 吗啡戒断期间体重减轻。 肽的作用 对吗啡的耐受性和依赖性的发展 将确定吗啡戒断症状。 DA的结合 受体配体 3H-SCH 23390 和 3H-多潘立酮（D1 和 D2 受体， 分别）和阿片受体配体，3H-DAMGO（mu），3H-DPDPE (sigma) 和 3H-U-69,593 (k) 至 CNS 区域（脊髓、杏仁核、 海马体、下丘脑、纹状体、脑桥和延髓、中脑和 大脑皮层）将被确定。 初步研究表明，在 耐受依赖性和戒断过程 DA 和阿片受体 CNS区域受到不同程度的影响，因此将进行研究 与特定的大脑区域。 为了确定 CNS 是否发生变化 DA 和阿片受体通过阿片机制介导 纳曲酮对这种变化的影响将被确定。 一旦DA的特异性 并且阿片受体发生变化，然后涉及第二个 信使系统（腺苷酸环化酶和磷酸肌醇）将 决定。 不同程度耐受性的影响 在不同时间间隔植入不同数量的颗粒 将监测上述生化参数。 肽的作用 脑室内给予吗啡耐受依赖性将是 确定建立中枢或外周作用机制。 测试 肽通过修饰 DA 抑制吗啡耐受的假设 阿片受体，它们对吗啡引起的特定变化的影响 CNS 的区域将被确定。 这些研究不仅可能导致 更好地了解阿片成瘾过程的机制，但 还致力于开发更安全的阿片类药物管理药物 成瘾和令人痛苦的戒断综合症。