NON-OPIOID DYNA:MOLECULAR/CELLULAR/PHYSIOLOGICAL STUDIES

产品说明：（申请人的摘要）这个程序项目的目的是阐明强啡肽衍生肽的药理学和结构-构象特性，介导非阿片样物质的作用，这可能是重要的，在了解药物滥用。这些作用包括：1）逆转吗啡耐受性和恢复阿片受体的脊髓-脊髓上协同作用（Lee）; 2）抑制对可卡因的致敏作用（Dworkin/Shippenberg）; 3）刺激胎儿垂体释放ACTH（Szeto）。 这些作用的非阿片类性质通过以下方式证明：a）它们对阿片类拮抗剂如纳洛酮和nor-BNI不敏感; B）它们通过强啡肽A-（2-17）介导，强啡肽A-（2-17）不与阿片类受体结合。 然而，这些系统中的每一个也表现出阿片受体的参与，这表明强啡肽可能在每个系统中发挥双重调节作用，通过阿片受体和非阿片受体起作用。已证明介导强啡肽这些作用的非阿片系统极其复杂，需要采用综合方法，其中药理学数据用于为结构-构象研究提供信息，这些研究旨在定义与一种或多种非阿片受体相互作用所需的强啡肽肽的关键特征（Weinstein）。对内源性强啡肽（Hook）的研究也将提供对结构要求的深入了解，强啡肽可能作为非阿片受体的配体发挥作用。 从这种多学科合作中获得的数据将定义非阿片类强啡肽系统，并使该计划能够进入第二阶段，其中受体将被克隆和表达。

DESCRIPTION: (Applicant's Abstract) The purpose of this program project is to elucidate the pharmacological and structural-conformational properties of dynorphin-derived peptides that mediate nonopioid effects that may be important in understanding drug abuse. These effects include 1) reversal of morphine tolerance and restoration of spinal-supraspinal synergism of opioid receptors (Lee); 2) inhibition of sensitization to cocaine (Dworkin/Shippenberg); and 3) stimulation of ACTH release from fetal pituitary (Szeto). The nonopioid nature of these effects is demonstrated by a) their insensitivity to opioid antagonists such as naloxone and nor-BNI; b) their mediation by dynorphinA-(2-17), which does not bind to opioid receptors. However, each of these systems also manifests involvement of opioid receptors, suggesting that dynorphin may play a dual regulatory role in each, acting through both opioid and nonopioid receptors. The nonopioid system(s) mediating these effects of dynorphin have proven extremely complex, necessitating an integrated approach in which pharmacological data are used to inform structural-conformational studies that are aimed at defining the critical features of the dynorphin peptide required for interacting with the(se) non-opioid receptor or receptors (Weinstein). Insight into structural requirements will also be provided by studies of dynorphin peptides present endogenously (Hook), which might function as ligands for the nonopioid receptor(s). The data obtained from this multidisciplinary collaboration will define the nonopioid dynorphin system and enable the program to move on to a second phase in which the receptors will be cloned and expressed.