NON-OPIOID DYNA:MOLECULAR/CELLULAR/PHYSIOLOGICAL STUDIES

（申请人摘要）本项目的目的是阐明能介导非阿片效应的肌啡衍生肽的药理学和结构构象性质，这可能对理解药物滥用有重要意义。这些作用包括1)吗啡耐受性逆转和阿片受体脊髓-棘上协同作用的恢复（Lee）；2)抑制可卡因致敏（Dworkin/Shippenberg）；3)刺激胎儿垂体ACTH释放（Szeto）。这些效应的非阿片类性质表现为：a)它们对阿片类拮抗剂如纳洛酮和非bni不敏感；b)它们由不与阿片受体结合的dynorphinA-(2-17)介导。然而，这些系统也表现出阿片受体的参与，这表明苦啡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。介导肌啡肽这些作用的非阿片系统已被证明是极其复杂的，需要一种综合的方法，其中使用药理学数据来为结构构象研究提供信息，旨在确定肌啡肽与（se）非阿片受体或受体相互作用所需的关键特征（Weinstein）。对内源性肌啡肽（Hook）的研究也将提供对结构要求的深入了解，肌啡肽可能作为非阿片受体的配体。从这一多学科合作中获得的数据将定义非阿片类激啡系统，并使该计划进入第二阶段，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.