EFFECTS OF SYSTEMICALLY ADMINISTERED DYNORPHINS

Kappa(K)-阿片配体由于以下原因重新受到关注 它们在治疗痛苦状况方面的潜力，以及它们治疗疼痛的能力 减弱精神刺激剂(如可卡因)的影响。的目标是 这些研究是为了检验中央假说强啡肽A(I-17)(An K受体内源性激动剂)和E-2078(一种稳定的强啡肽A(1-8)) 类似物)是高效、外周选择性激动剂，在建议的 恒河猴全身给药后的“k”亚型阿片受体。 有几项研究集中在中枢神经系统后强啡肽的药理学 对啮齿类动物的管理。相比之下，系统性的影响 在猴子身上使用强啡肽还没有得到广泛的研究，可能是 由于质量和数量的相似性，具有特殊的临床相关性 在非人类灵长类动物和人类中的k受体种群之间。研究到 数据显示，全身注射的强啡肽会产生一些，但不是全部 在灵长类动物中通常与非肽性K-激动剂相关的作用， 包括人类。这一点特别有趣，因为临床上使用 选择性非肽性k-激动剂因其不良作用而受到限制。 (例如，镇静和烦躁的主观效果)。强啡肽可能会产生 临床上相关的影响(例如，抗过敏)，程度较轻或较轻 不良影响。静脉给药的兴奋作用 因此，强啡肽A(I-17)和E-2078将在分析中得到表征 热抗伤害性感觉和辣椒素诱导的热过敏，以及在一个 神经内分泌终点，血清催乳素水平升高。催乳素水平 可作为全身强啡肽的一种敏感的定量标志物 人类和非人类灵长类动物的药理学。肌动蛋白受体的调节作用 强啡肽在上述所有化验中的作用将通过以下方法进行初步研究 阿片类拮抗剂(纳曲酮及其外周选择性 模拟，四元纳曲酮)。总体而言，强啡肽A(I-I 7)和E-2078将 与非阿片类片段强啡肽A(2-17)相比，具有亚型选择性 K-阿片配体(U69,593和灯盏花素)和部分K-激动剂 (纳洛芬)。具体地说，我们的目标是确定强啡肽是否明显 疗效、建议的外周选择性和建议的k亚型 选择性可能与它们在灵长类动物体内的分布有关(因此 他们的临床潜力)。

Kappa (k)- opioid ligands have received renewed attention due to their potential in the treatment of painful conditions, and their ability to attenuate the effects of psychostimulants (e.g., cocaine). The objective of these studies is to test the Central Hypothesis that dynorphin A(I-17) (an endogenous agonist at k-receptors), and E-2078 (a stable dynorphin A(1-8) analog), are high efficacy, peripherally selective agonists at the proposed "k," subtype opioid receptors, after systemic administration in rhesus monkeys. Several studies have focused on dynorphin pharmacology after central administration in rodents. In contrast, the effects of systemically administered dynorphins in monkeys have not been widely studied, and may be of particular clinical relevance, due to qualitative and quantitative similarities between k-receptor populations in non-human primates and humans. Studies to date reveal that systemically administered dynorphins produce some, but not all the effects commonly associated with non-peptidic k-agonists in primates, including humans. This is of particular interest, because clinical use of selective non-peptidic k-agonists has been limited by their undesirable effects (e.g., sedation and dysphoric subjective effects). The dynorphins may produce clinically relevant effects (e.g., anti-allodynia), with fewer or less severe undesirable effects. The agonist actions of intravenously administered dynorphin A(I-17) and E-2078 will therefore be characterized in assays ofthermal antinociception and capsaicin-induced thermal allodynia, and in a neuroendocrine endpoint, increases in serum prolactin levels. Prolactin levels can be used as a sensitive, quantitative marker of systemic dynorphin pharmacology in human and non-human primates. The receptor mediation of dynorphin effects in all the above assays will be initially studied by pretreatment with opioid antagonists (naltrexone and its peripherally selective analog, quaternary naltrexone). Overall, dynorphin A(I-I 7) and E-2078 will be compared to the non-opioid fragment, dynorphin A(2-17), to subtype-selective k-opioid ligands (U69,593 and bremazocine) and to a partial k-agonist (nalorphine). Specifically, we aim to determine whether the dynorphins'apparent efficacy, their proposed peripheral selectivity and their proposed k-subtype selectivity may be relevant to their in vivo profile in primates (and thus their clinical potential).