Following the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) as an endogenous ligand for the NOP receptor, ample evidence has revealed unique functional profiles of the N/OFQ-NOP receptor system. NOP receptors are expressed in key neural substrates involved in pain and reward modulation. In nonhuman primates (NHPs), NOP receptor activation effectively exerts antinociception and anti-hypersensitivity at the spinal and supraspinal levels. Moreover, NOP receptor activation inhibits dopaminergic transmission and synergistically enhances mu-opioid peptide (MOP) receptor-mediated analgesia. In this article, we have discussed the functional profiles of ligands with dual NOP and MOP receptor agonist activities and highlight their optimal functional efficacy for pain relief and drug abuse treatment. Through coactivation of NOP and MOP receptors, bifunctional NOP/MOP receptor “partial” agonists (e.g., AT-121, BU08028, and BU10038) reveal a wider therapeutic window with fewer side effects. These newly developed ligands potently induce antinociception without MOP receptor agonist-associated side effects such as abuse potential, respiratory depression, itching sensation, and physical dependence. In addition, in both rodent and NHP models, bifunctional NOP/MOP receptor agonists can attenuate reward processing and/or the reinforcing effects of opioids and other abused drugs. While a mixed NOP/opioid receptor “full” agonist cebranopadol is undergoing clinical trials, bifunctional NOP/MOP “partial” agonists exhibit promising therapeutic profiles in translational NHP models for the treatment of pain and opioid abuse. This class of drugs demonstrates the therapeutic advantage of NOP and MOP receptor coactivation, indicating a greater potential for future development.

中文翻译：

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NOP 和 MOP 受体共激活治疗疼痛和阿片类药物滥用的治疗潜力

在将伤害感受素/孤儿啡肽 FQ (N/OFQ) 肽 (NOP) 鉴定为 NOP 受体的内源性配体之后，大量证据揭示了 N/OFQ-NOP 受体系统的独特功能特征。NOP 受体在参与疼痛和奖赏调节的关键神经基质中表达。在非人类灵长类动物 (NHP) 中，NOP 受体激活有效地在脊髓和脊髓上水平发挥镇痛和抗过敏作用。此外，NOP 受体激活抑制多巴胺能传递并协同增强 mu-阿片肽 (MOP) 受体介导的镇痛作用。在本文中，我们讨论了具有双重 NOP 和 MOP 受体激动剂活性的配体的功能概况，并强调了它们在缓解疼痛和药物滥用治疗方面的最佳功能功效。通过 NOP 和 MOP 受体的共激活，双功能 NOP/MOP 受体“部分”激动剂（例如，AT-121、BU08028 和 BU10038）揭示了更宽的治疗窗和更少的副作用。这些新开发的配体有效地诱导镇痛，而没有与 MOP 受体激动剂相关的副作用，例如滥用潜力、呼吸抑制、瘙痒感和身体依赖。此外，在啮齿动物和 NHP 模型中，双功能 NOP/MOP 受体激动剂可以减弱奖励处理和/或阿片类药物和其他滥用药物的增强作用。虽然混合 NOP/阿片受体“完全”激动剂 cebranopadol 正在进行临床试验，但双功能 NOP/MOP“部分”激动剂在用于治疗疼痛和阿片类药物滥用的转化 NHP 模型中表现出有希望的治疗特征。