Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-5632, USA Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center, National Institute of Neuroscience, University of Ferrara, 44100 Ferrara, Italy Department of Pharmaceutical Sciences, Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy Department of Psychology, Institute of Neuroscience, National Cheng-Chi University, Taipei 11605, Taiwan.
Pain. 2010 Jan;148(1):107-113. doi: 10.1016/j.pain.2009.10.026. Epub 2009 Nov 28.
Chemical modifications 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-NH(2) (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological profile 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 (0.1mg/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 4-5h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced significant 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.
最近，对孤啡肽（N/OFQ）肽进行的化学修饰导致其效力增加且对降解的抵抗力增强，从而发现了新型孤啡肽（NOP）受体激动剂[(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2)（UFP-112）。本研究旨在通过不同的行为学检测，研究鞘内给予 UFP-112 对猴子的药理学特征。鞘内给予 UFP-112（1-10nmol）剂量依赖性地对急性伤害性刺激（50°C 水）和辣椒素诱导的热痛觉过敏产生镇痛作用。鞘内给予 UFP-112 引起的镇痛作用可被 NOP 受体拮抗剂 J-113397（0.1mg/kg）逆转，但不能被经典阿片受体拮抗剂纳洛酮（0.03mg/kg）逆转。与鞘内给予吗啡相似，UFP-112 在两种灵长类动物疼痛模型中产生镇痛作用，其有效性相当，作用持续时间相似，为 4-5 小时。与鞘内给予吗啡不同，UFP-112 不会引起瘙痒/搔抓反应。此外，鞘内给予无效剂量的 UFP-112 和吗啡联合使用时，会产生显著的镇痛作用，而不会增加搔抓反应。这些结果表明，鞘内给予 UFP-112 可产生与吗啡相当的长效镇痛作用，而无潜在的瘙痒副作用。本研究首次提供了功能证据，即选择性 NOP 受体激动剂，如 UFP-112 单独或与吗啡联合使用，可能改善脊髓镇痛的质量。
