NON-OPIOID DYNA:MOLECULAR/CELLULAR/PHYSIOLOGICAL STUDIES

描述：(申请人摘要)该计划项目的目的是阐明强啡肽衍生的多肽的药理和结构构象特性，这些多肽介导的非阿片类药物效应可能对理解药物滥用很重要。这些效应包括：1)逆转吗啡耐受，恢复脊髓-脊髓上阿片受体的协同作用(Lee)；2)抑制对可卡因的增敏作用(Dworkin/Shippenberg)；3)刺激胎儿脑下垂体释放ACTH(Szeto)。这些效应的非阿片性质表现为：a)它们对阿片拮抗剂如纳洛酮和Nor-BNI不敏感；b)它们由强啡肽A-(2-17)介导，强啡肽A-(2-17)不与阿片受体结合。然而，这些系统中的每一个也都显示了阿片受体的参与，这表明强啡肽可能在每个系统中发挥双重调节作用，既通过阿片受体又通过非阿片受体发挥作用。介导强啡肽这些作用的非阿片系统(S)被证明是极其复杂的，需要一种综合的方法，其中药理学数据被用来为结构构象研究提供信息，这些研究旨在确定与(Se)非阿片受体相互作用所需的强啡肽的关键特征(WEINSTER)。对内源性存在的强啡肽(Hook)的研究也将提供对结构要求的洞察，这些多肽可能作为非阿片受体的配体(S)。从这一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，在该阶段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.