Central N/OFQ-NOP Receptor System in Pain Modulation.
Central N/OFQ-NOP Receptor System in Pain Modulation.
复制标题
DOI：
10.1016/bs.apha.2015.10.001
复制
发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Ko MC
中科院分区：
文献类型：
--
作者：
Kiguchi N;Ding H;Ko MC
孤啡肽（N/OFQ）及其同源受体（NOP）被发现至今已有20年的历史。尽管NOP受体激活引起与μ阿片样物质（MOP）受体类似的细胞内作用模式，但啮齿动物中NOP受体介导的疼痛调节比MOP受体激活更复杂。在这篇综述中，我们强调了NOP受体激动剂调节疼痛的脊髓，脊髓上和全身作用的功能证据。在啮齿类动物中，N/OFQ-NOP受体系统在脊髓和脊髓上部位调节疼痛的作用是双向的，这取决于剂量、测定和疼痛模式。全身施用的NOP受体激动剂的净效应可能取决于在不同疼痛状态下啮齿动物中N/OFQ-NOP受体信号传导的脊髓和脊髓上作用的相对贡献。与此形成鲜明对比的是，NOP受体激动剂在非人灵长类动物的脊髓和脊髓上区域仅产生抗伤害感受和抗超敏反应，而与剂量和测定无关。更重要的是，NOP受体激动剂和一些双功能NOP/MOP受体激动剂在非人灵长类动物中不表现出强化作用（滥用倾向）、呼吸抑制、瘙痒，也不延迟胃肠转运功能（便秘）。根据其激活NOP和MOP受体的内在功效，双功能NOP/MOP受体激动剂需要在灵长类动物中对其副作用特征进行额外研究。然而，与灵长类动物中的MOP受体激动剂相比，NOP受体相关激动剂显示出宽得多的治疗窗口。选择性NOP受体激动剂和双功能NOP/MOP受体激动剂作为有效和安全的镇痛剂在人类中没有典型的阿片类药物相关的副作用，具有很大的潜力。
It has been two decades since the peptide, nociceptin/orphanin FQ (N/OFQ), and its cognate (NOP) receptor were discovered. Although NOP receptor activation causes a similar pattern of intracellular actions as mu opioid (MOP) receptors, NOP receptor-mediated pain modulation in rodents are more complicated than MOP receptor activation. In this review, we highlight the functional evidence of spinal, supraspinal, and systemic actions of NOP receptor agonists for regulating pain. In rodents, effects of the N/OFQ-NOP receptor system in spinal and supraspinal sites for modulating pain are bidirectional depending on the doses, assays, and pain modalities. The net effect of systemically administered NOP receptor agonists may depend on relative contribution of spinal and supraspinal actions of the N/OFQ-NOP receptor signaling in rodents under different pain states. In stark contrast, NOP receptor agonists produce only antinociception and antihypersensitivity in spinal and supraspinal regions of nonhuman primates regardless of doses and assays. More importantly, NOP receptor agonists and a few bifunctional NOP/MOP receptor agonists do not exhibit reinforcing effects (abuse liability), respiratory depression, itch pruritus, nor do they delay the gastrointestinal transit function (constipation) in nonhuman primates. Depending upon their intrinsic efficacies for activating NOP and MOP receptors, bifunctional NOP/MOP receptor agonists warrant additional investigation in primates regarding their side effect profiles. Nevertheless, NOP receptor-related agonists display a much wider therapeutic window as compared to that of MOP receptor agonists in primates. Both selective NOP receptor agonists and bifunctional NOP/MOP receptor agonists hold a great potential as effective and safe analgesics without typical opioid-associated side effects in humans.