Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.

中文翻译：

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Nociceptin/Orphanin FQ 肽受体相关配体作为新型镇痛药。

尽管在伤害感受素/孤儿蛋白 FQ 肽 (NOP) 受体和其他阿片受体中观察到类似的分布模式和细胞内事件，但 NOP 受体激活显示出独特的药理学特征。几位研究人员已经确定了多种肽和非肽配体来确定 NOP 受体激活的功能作用，并观察到 ​​NOP 受体相关配体表现出疼痛方式依赖的疼痛处理。重要的是，无论非人类灵长类动物 (NHP) 的实验环境如何，NOP 受体激活都会导致脊髓和脊髓上水平的抗伤害感受和抗超敏反应。鉴于 NOP 受体激动剂协同增强 μ-阿片肽 (MOP) 受体激动剂诱导的抗伤害感受，据推测，NOP 和 MOP 双重受体激动剂作为镇痛剂可能显示出有前景的功能特性。越来越多的证据表明，混合的 NOP/阿片受体激动剂表现出良好的功能特性。在 NHP 研究中，双功能 NOP/MOP 部分激动剂（例如，AT-121、BU08028 和 BU10038）通过 NOP 和 MOP 受体激活发挥有效的抗伤害感受作用；然而，没有观察到与 MOP 受体激活相关的剂量限制性副作用，包括呼吸抑制、瘙痒感、身体依赖性和滥用倾向。此外，混合 NOP/阿片受体激动剂，cebranopadol，作为一种新型镇痛剂，在临床试验中取得了可喜的成果。总的来说，对 NOP 和 MOP 受体的双重激动作用，具有适当的结合亲和力和功效，