Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse.
Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse.
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DOI：
10.1002/jnr.24624
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发表时间：
2022-01
影响因子：
4.2
通讯作者：
Ko MC
中科院分区：
文献类型：
--
作者：
Kiguchi N;Ding H;Ko MC
在鉴定出伤害感受素/N-孤啡肽（N/OFQ）肽（NOP）作为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。在非人灵长类动物（NHP）中，NOP受体激活在脊髓和脊髓上水平有效地发挥抗伤害感受和抗超敏反应作用。此外，NOP受体活化抑制多巴胺能传递并协同增强μ阿片肽（MOP）受体介导的镇痛。在这篇文章中，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，并强调了其用于缓解疼痛和药物滥用治疗的最佳功能功效。通过NOP和MOP受体的共活化，双功能NOP/MOP受体“部分”激动剂（例如，AT-121、BU 08028和BU 10038）显示了更宽的治疗窗，副作用更少。这些新开发的配体有效地诱导抗伤害感受，而没有MOP受体激动剂相关的副作用，如滥用潜力、呼吸抑制、瘙痒感和身体依赖性。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阿片类药物和其他滥用药物的奖赏处理和/或强化作用。虽然混合的NOP/阿片受体“完全”激动剂西博帕多正在进行临床试验，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翻译NHP模型中表现出有希望的治疗概况。这类药物证明了NOP和MOP受体共激活的治疗优势，表明未来开发的潜力更大。
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 non-human 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 discuss 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, itch 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.
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