EFFECTS OF SYSTEMICALLY ADMINISTERED DYNORPHINS

全身使用强啡肽的作用

• 批准号: 6515586
• 负责人: EDUARDO R BUTELMAN
• 金额: $ 33.48万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-29 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515586
• 关键词: Macaca mulatta; NMDA receptors; analgesics; biotransformation; capsaicin; drug hypersensitivity; drug interactions; drug screening /evaluation; dynorphins; hyperalgesia; nalorphine; naltrexone; opioid receptor; pain; peptide analog; prolactin; psychomotor function; psychopharmacology; respiratory pharmacology; self medication; sensory depression; urinalysis

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).

Kappa（k）-阿片样物质配体由于以下原因而重新受到关注： 他们在治疗疼痛方面的潜力，以及他们的能力， 减弱精神兴奋剂的作用（例如，可卡因）。的目标 这些研究是为了验证强啡肽A（I-17）（一种 K受体的内源性激动剂）和E-2078（一种稳定的强啡肽A（1-8） 类似物），是高效率，外周选择性激动剂，在建议的 “k”亚型阿片受体，在恒河猴中全身给药后。 几项研究集中在中枢神经系统损伤后的强啡肽药理学上。 在啮齿类动物中施用。相反，系统性的影响 在猴子中施用强啡肽尚未被广泛研究，并且可能是 由于定性和定量相似性，具有特殊的临床相关性 在非人类灵长类动物和人类的k受体群体之间。研究来 数据显示，系统给予强啡肽产生一些，但不是全部， 灵长类动物中通常与非肽k-激动剂相关的影响， 包括人类这是特别令人感兴趣的，因为临床使用 选择性的非肽类κ-激动剂受到其不良作用的限制 (e.g.,镇静和烦躁的主观效应）。强啡肽可以产生 临床相关效应（例如，抗异常性疼痛），严重程度更低或更轻 不良影响。静脉注射的激动剂作用 因此，强啡肽A（I-17）和E-2078将在测定中表征 热抗伤害感受和辣椒素诱导的热异常性疼痛， 神经内分泌终点，血清催乳素水平升高。催乳素水平 可用作系统性强啡肽的敏感、定量标记物 人类和非人类灵长类动物的药理学。受体介导 强啡肽在所有上述试验中的作用将首先通过以下方法进行研究： 用阿片类拮抗剂（纳洛酮及其外周选择性 类似物，季纳洛酮）。总的来说，强啡肽A（I-I7）和E-2078将是 与非阿片片段强啡肽A（2-17）相比， k-阿片配体（U69、593和布马佐辛）和部分k-激动剂 （纳洛啡）。具体来说，我们的目标是确定强啡肽是否明显 有效性、拟定的外周选择性和拟定的k亚型 选择性可能与它们在灵长类动物中的体内分布有关（因此 临床潜力）。

项目成果

Nicotine addiction: insights from recent animal studies.

尼古丁成瘾：来自最近动物研究的见解。

• DOI: 10.1007/s00213-002-1096-0
• 发表时间: 2002
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Mathieu-Kia,AM;Kellogg,SH;Butelman,ER;Kreek,MJ
• 通讯作者: Kreek,MJ

Semisynthetic neoclerodanes as kappa opioid receptor probes.

• DOI: 10.1016/j.bmc.2012.02.040
• 发表时间: 2012-05-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Lovell, Kimberly M.;Vasiljevik, Tamara;Araya, Juan J.;Lozama, Anthony;Prevatt-Smith, Katherine M.;Day, Victor W.;Dersch, Christina M.;Rothman, Richard B.;Butelman, Eduardo R.;Kreek, Mary Jeanne;Prisinzano, Thomas E.
• 通讯作者: Prisinzano, Thomas E.

Bidirectional translational research: Progress in understanding addictive diseases.

• DOI: 10.1016/j.neuropharm.2008.07.042
• 发表时间: 2009
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Kreek MJ;Schlussman SD;Reed B;Zhang Y;Nielsen DA;Levran O;Zhou Y;Butelman ER
• 通讯作者: Butelman ER

Discriminative Stimulus Properties of Opioid Ligands: Progress and Future Directions.

• DOI: 10.1007/7854_2016_9
• 发表时间: 2016-05
• 期刊: Current topics in behavioral neurosciences
• 作者: E. Butelman;M. Kreek

kappa-Opioid receptor binding populations in rhesus monkey brain: relationship to an assay of thermal antinociception.

• 发表时间: 1998-05
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: E. Butelman;M. Ko;K. Sobczyk‐Kojiro;H. Mosberg;B. V. van Bemmel;G. Zernig;J. Woods