SYSTEMICALLY ADMINISTERED DYNORPHINS

强啡肽包括内源性阿片肽如强啡肽 A1 -17和强啡肽A的片段，以及基于 强啡肽结构强啡肽A被认为是内源性的 K型阿片受体的配体，许多强啡肽也是如此。 显示K-选择性作用曲线。大多数研究检查体内 强啡肽的作用已经检查了中枢（例如， 脑室内或鞘内）施用强啡肽， 啮齿类动物;这些化合物全身给药的作用， 其他物种，特别是灵长类动物，还没有得到很好的研究。 这些研究是重要的，因为1）临床上有用的药物是理想的 全身给药后有活性，2）啮齿类动物可能没有 潜在K选择性临床前评价的最佳种属 化合物，因为它们已被证明具有K 这些受体在数量和质量上与那些 在灵长类中发现的。强啡肽是一组化合物 特别值得这样的审查，因为初步实验 表明强啡肽1-13全身（iv）给药和 最近开发的强啡肽类似物E-2078可能产生镇痛作用 没有烦躁的主观影响，阻碍了临床 生物碱K激动剂的应用。拟议的实验将 通过详细检查A的激动剂作用， 在恒河猴中系统给予强啡肽的系列研究， 抗伤害感受的测定（温水尾浸法和 前列腺素E2诱导的痛觉过敏/异常性疼痛）、药物辨别 （训练猴子区分E-2078与盐水或K激动剂） U69，593来自盐水），食物强化的操作性反应（训练的猴子 根据FR 3 O食物强化计划做出反应）， （肌肉松弛和镇静的观察评定量表），利尿 （三小时测试期间的排尿量）和强化 （在接受阿芬太尼自我给药训练的猴子中进行替代）。任何 将评价激动剂作用对拮抗作用的敏感性， μ-选择性阿片拮抗剂quadazocine，K-选择性拮抗剂 nor-binaltorphimine，如果需要，还可以使用δ选择性拮抗剂 纳曲吲哚这些研究的结果应该揭示了 强啡肽家族的哪些原型成员有着相似的 具有临床应用潜力的激动剂作用概况。在 此外，这些研究将提供与识别 系统性强啡肽活性的结构要求， 为新化合物的设计和合成提供信息。最后，这些研究 将确定K阿片受体在介导 全身给予强啡肽。

The dynorphins comprise both endogenous opioid peptides such as dynorphin A 1-17 and fragments of dynorphin A, as well as peptide analogs based on the dynorphin structure. Dynorphin A has been proposed as the endogenous ligand for the K type of opioid receptor, and many of the dynorphins do show K-selective profiles of action. Most studies examining the in vivo effects of the dynorphins have examined the effects of the central (eg. intracerebroventricular or intrathecal) administration of dynorphins in rodents; the effect of systemic administration of these compounds in other species, and especially in primates, has not been well studied. Such studies are important since 1) clinically-useful drugs are ideally active following systemic administration and 2)rodents are probably not the best species for the preclinical evaluation of potential K-selective compounds since they have been shown to possess populations of K receptors that are quantitatively and qualitatively distinct from those found in primates. The dynorphins have emerged as a set of compounds especially deserving of such scrutiny since preliminary experiments indicate that systemic (iv) administration of dynorphin 1-13 and the recently-developed dynorphin analog E-2078 may produce analgesic effects without the dysphoric subjective effects that have impeded the clinical application of the alkaloid K agonists. The proposed experiments will follow up on this lead by examining in detail the agonist effects of a series of systemically-administered dynorphins in rhesus monkeys in assays of antinociception (warm-water tail-dip procedure and prostaglandin E2-induced hyperalgesia/allodynia), drug discrimination (monkeys trained to discriminate E-2078 from saline or the K agonist U69,593 from saline), food-reinforced operant responding (monkeys trained to respond under FR3O schedule of food reinforcement), gross behavior (observational rating scales of muscle relaxation and sedation), diuresis (volume of urination during three-hour test sessions) and reinforcement (substitution in monkeys trained to self-administer alfentanil). Any agonist effects will be evaluated for susceptibility to antagonism by the mu-selective opioid antagonist quadazocine, the K-selective antagonist nor-binaltorphimine, and, if warranted, the delta-selective antagonist naltrindole. The results of the these studies should reveal the degree to which prototypical members of the dynorphin family share a similar profile of agonist effects with potential for clinical application. In addition, these studies will provide information relevant to identifying the structural requirements for systemic dynorphin activity, which will inform the design and synthesis of new compounds. Finally, these studies will determine the role of K opioid receptors in mediating the effects of systemically-administered dynorphins.