Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112
Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112
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DOI：
10.1016/j.pain.2009.10.026
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发表时间：
2010-01-01
期刊：
影响因子：
7.4
通讯作者：
Ko, Mei-Chuan
中科院分区：
文献类型：
--
作者：
Hu, Eric;Calo, Girolamo;Ko, Mei-Chuan
化学莫迪。nociceptin/ orphin FQ （N/OFQ）肽的阳离子导致效力增强和降解抗性，最近导致发现[(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ- nh2 (UFP-112)，一种新型N/OFQ肽（NOP）受体激动剂。本研究的目的是探讨其药理作用。在不同行为分析下，对猴子进行鞘内注射UFP-112的研究。鞘内UFP-112 （1-10 nmol）剂量依赖性地产生抗急性有害刺激（50℃水）和辣椒素诱导的热痛觉过敏。鞘内ufp -112诱导的抗痛感可被NOP受体拮抗剂J-113397 （0.1 mg/kg）逆转，但不能被经典阿片受体拮抗剂纳曲酮（0.03 mg/kg）逆转。与鞘内吗啡一样，UFP-112在两种灵长类动物疼痛模型中产生抗痛觉作用，其有效性和持续时间相似，持续时间为4-5小时。与鞘内吗啡不同，UFP-112不产生瘙痒/抓痒反应。此外，鞘内注射无活性剂量的UFP-112和吗啡在不增加抓伤反应的情况下产生显著的抗伤感受作用。这些结果表明鞘内UFP-112产生持久的与吗啡相当的抗痛觉作用，而没有潜在的瘙痒副作用。本研究首次提供功能性证据，证明选择性NOP受体激动剂如UFP-112单独使用或与吗啡联合使用可改善脊髓镇痛质量。(C) 2009年国际疼痛研究协会。Elsevier b.v.版权所有。
Chemical modi. cations of nociceptin/orphanin FQ (N/OFQ) peptide that result in increased potency and resistance to degradation have recently lead to the discovery of [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH2 (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological pro. le of intrathecally administered UFP-112 in monkeys under different behavioral assays. Intrathecal UFP-112 (1-10 nmol) dose-dependently produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced thermal hyperalgesia. Intrathecal UFP-112-induced antinociception could be reversed by a NOP receptor antagonist, J-113397 (0.1 mg/kg), but not by a classic opioid receptor antagonist, naltrexone (0.03 mg/kg). Like intrathecal morphine, UFP-112 produced antinociception in two primate pain models with a similar magnitude of effectiveness and a similar duration of action that last for 4-5 h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced signi.cant antinociceptive effects when given in combination without increasing scratching responses. These results demonstrated that intrathecal UFP-112 produced long-lasting morphine-comparable antinociceptive effects without potential itch side effect. This study is the first to provide functional evidence that selective NOP receptor agonists such as UFP-112 alone or in conjunction with morphine may improve the quality of spinal analgesia. (C) 2009 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.