Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
Division of Neurobiology and Behavior Research, Department of Psychiatry and Human Behavior, The University of Mississippi Medical Center, Jackson, MS, USA.
Handb Exp Pharmacol. 2022;271:137-162. doi: 10.1007/164_2021_443.
Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.
那呋拉啡在日本已被用于治疗肾透析患者和慢性肝病患者的瘙痒，并进行了为期一年的上市后研究，结果表明那呋拉啡既安全又有效，且没有典型 κ 阿片受体激动剂（如快感缺失和幻觉）的副作用。在本章中，我们总结了那呋拉啡的体外特征和体内临床前研究。体外研究表明，那呋拉啡是一种高效、中度选择性的 κ 阿片受体完全激动剂；但它是否是一种偏向性 κ 阿片受体激动剂仍存在争议。在动物模型中，那呋拉啡在产生止痒作用的剂量范围内，不会引起不良反应，包括条件性位置厌恶（CPA）、运动减少、运动不协调，这与人类数据一致。此外，那呋拉啡在几种疼痛模型中显示出镇痛作用，且剂量不会引起上述不良反应。它似乎对炎症性疼痛和机械性疼痛有效，但对热痛，尤其是高强度热痛效果较差。U50,488H 和那呋拉啡以脑区特异性方式差异调节几种信号通路。值得注意的是，U50,488H 而非那呋拉啡激活了 mTOR 通路，这有助于 U50,488H 诱导的 CPA。由于缺乏与典型 κ 阿片受体激动剂相关的副作用，那呋拉啡已被作为与 μ 阿片受体配体联合治疗疼痛、治疗阿片类药物使用障碍和酒精使用障碍的候选药物，研究结果表明该药对这些适应证具有潜在的应用价值。因此，尽管那呋拉啡在 κ 阿片受体信号转导方面的体外数据存在一些争议，但体内结果支持这样的观点，即那呋拉啡是一种非典型 κ 阿片受体激动剂，与典型 κ 阿片受体激动剂相比，具有显著改善的副作用谱。
