Kiguchi Norikazu, Ko Mei-Chuan
Department of Pharmacology, Wakayama Medical University, Wakayama, Japan.
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Handb Exp Pharmacol. 2019;254:323-343. doi: 10.1007/164_2019_211.
The nociceptin/orphanin FQ peptide (NOP) receptor-related ligands have been demonstrated in preclinical studies for several therapeutic applications. This article highlights (1) how nonhuman primates (NHP) were used to facilitate the development and application of positron emission tomography tracers in humans; (2) effects of an endogenous NOP ligand, nociceptin/orphanin FQ, and its interaction with mu opioid peptide (MOP) receptor agonists; and (3) promising functional profiles of NOP-related agonists in NHP as analgesics and treatment for substance use disorders. NHP models offer the most phylogenetically appropriate evaluation of opioid and non-opioid receptor functions and drug effects. Based on preclinical and clinical data of ligands with mixed NOP/MOP receptor agonist activity, several factors including their intrinsic efficacies for activating NOP versus MOP receptors and different study endpoints in NHP could contribute to different pharmacological profiles. Ample evidence from NHP studies indicates that bifunctional NOP/MOP receptor agonists have opened an exciting avenue for developing safe, effective medications with fewer side effects for treating pain and drug addiction. In particular, bifunctional NOP/MOP partial agonists hold a great potential as (1) effective spinal analgesics without itch side effects; (2) safe, nonaddictive analgesics without opioid side effects such as respiratory depression; and (3) effective medications for substance use disorders.
伤害感受素/孤啡肽FQ肽（NOP）受体相关配体已在多项治疗应用的临床前研究中得到证实。本文重点介绍了：（1）非人灵长类动物（NHP）如何被用于促进正电子发射断层扫描示踪剂在人类中的开发和应用；（2）内源性NOP配体伤害感受素/孤啡肽FQ的作用及其与μ阿片肽（MOP）受体激动剂的相互作用；以及（3）NHP中NOP相关激动剂作为镇痛药和物质使用障碍治疗药物的有前景的功能概况。NHP模型为阿片类和非阿片类受体功能及药物作用提供了系统发育上最合适的评估。基于具有NOP/MOP受体混合激动剂活性的配体的临床前和临床数据，包括它们激活NOP与MOP受体的内在效能以及NHP中不同的研究终点等几个因素，可能导致不同的药理学特征。NHP研究的充分证据表明，双功能NOP/MOP受体激动剂为开发治疗疼痛和药物成瘾的副作用更少的安全、有效药物开辟了一条令人兴奋的途径。特别是，双功能NOP/MOP部分激动剂具有巨大潜力，可作为：（1）无瘙痒副作用的有效脊髓镇痛药；（2）无呼吸抑制等阿片类副作用的安全、非成瘾性镇痛药；以及（3）治疗物质使用障碍的有效药物。
