Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
Department of Physiological Sciences, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, 640-8156, Japan.
Drugs. 2023 Jun;83(9):771-793. doi: 10.1007/s40265-023-01878-5. Epub 2023 May 20.
As clinical use of currently available opioid analgesics is often impeded by dose-limiting adverse effects, such as abuse liability and respiratory depression, new approaches have been pursued to develop safe, effective, and non-addictive pain medications. After the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor more than 25 years ago, NOP receptor-related agonists have emerged as a promising target for developing novel and effective opioids that modulate the analgesic and addictive properties of mu-opioid peptide (MOP) receptor agonists. In this review, we highlight the effects of the NOP receptor-related agonists compared with those of MOP receptor agonists in experimental rodent and more translational non-human primate (NHP) models and the development status of key NOP receptor-related agonists as potential safe and non-addictive analgesics. Several lines of evidence demonstrated that peptidic and non-peptidic NOP receptor agonists produce potent analgesic effects by intrathecal delivery in NHPs. Moreover, mixed NOP/MOP receptor partial agonists (e.g., BU08028, BU10038, and AT-121) display potent analgesic effects when administered intrathecally or systemically, without eliciting adverse effects, such as respiratory depression, itch behavior, and signs of abuse liability. More importantly, cebranopadol, a mixed NOP/opioid receptor agonist with full efficacy at NOP and MOP receptors, produces robust analgesic efficacy with reduced adverse effects, conferring promising outcomes in clinical studies. A balanced coactivation of NOP and MOP receptors is a strategy that warrants further exploration and refinement for the development of novel analgesics with a safer and effective profile.
由于目前可用的阿片类镇痛药的临床应用常受到剂量限制的不良反应的阻碍，如滥用倾向和呼吸抑制，因此人们寻求新的方法来开发安全、有效且无成瘾性的疼痛药物。在 25 多年前发现孤啡肽/N 端前体（N/OFQ）肽（NOP）受体后，NOP 受体相关激动剂已成为开发新型有效阿片类药物的有前途的靶点，这些药物可调节μ-阿片肽（MOP）受体激动剂的镇痛和成瘾特性。在这篇综述中，我们重点介绍了 NOP 受体相关激动剂与 MOP 受体激动剂在实验性啮齿动物和更具转化意义的非人类灵长类动物（NHP）模型中的作用，并介绍了作为潜在安全且无成瘾性镇痛剂的关键 NOP 受体相关激动剂的开发状况。有几条证据表明，肽类和非肽类 NOP 受体激动剂通过鞘内给药在 NHP 中产生有效的镇痛作用。此外，混合 NOP/MOP 受体部分激动剂（例如，BU08028、BU10038 和 AT-121）鞘内或全身给药时具有有效的镇痛作用，而不会引起呼吸抑制、瘙痒行为和滥用倾向等不良反应。更重要的是，混合 NOP/阿片受体激动剂塞布诺肽对 NOP 和 MOP 受体具有完全疗效，在降低不良反应的同时产生强大的镇痛疗效，在临床研究中显示出良好的结果。NOP 和 MOP 受体的平衡共激活是一种值得进一步探索和完善的策略，以开发具有更安全有效特性的新型镇痛药。
