Departments of Physiology and Pharmacology (S.W.K., A.N.W., J.D.G., K.W., D.P.S., V.S.), Neuroscience, and Behavioral Medicine and Psychiatry (V.S.), West Virginia University School of Medicine, Morgantown, West Virginia; Department of Psychology, West Virginia University Eberly College of Arts and Sciences, Morgantown, West Virginia (K.R.T., S.G.K.); Department of Medicinal Chemistry, The University of Kansas School of Pharmacy, Lawrence, Kansas (T.E.P.); Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina (A.A.H., J.A.); and Department of Pharmacology, The University of North Carolina School of Medicine, Chapel Hill, North Carolina (T.K.).
Departments of Physiology and Pharmacology (S.W.K., A.N.W., J.D.G., K.W., D.P.S., V.S.), Neuroscience, and Behavioral Medicine and Psychiatry (V.S.), West Virginia University School of Medicine, Morgantown, West Virginia; Department of Psychology, West Virginia University Eberly College of Arts and Sciences, Morgantown, West Virginia (K.R.T., S.G.K.); Department of Medicinal Chemistry, The University of Kansas School of Pharmacy, Lawrence, Kansas (T.E.P.); Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina (A.A.H., J.A.); and Department of Pharmacology, The University of North Carolina School of Medicine, Chapel Hill, North Carolina (T.K.)
J Pharmacol Exp Ther. 2019 Nov;371(2):487-499. doi: 10.1124/jpet.118.255661. Epub 2019 Sep 6.
Mu opioid receptor (MOR)-targeting analgesics are efficacious pain treatments, but notorious for their abuse potential. In preclinical animal models, coadministration of traditional kappa opioid receptor (KOR)-targeting agonists with MOR-targeting analgesics can decrease reward and potentiate analgesia. However, traditional KOR-targeting agonists are well known for inducing antitherapeutic side effects (psychotomimesis, depression, anxiety, dysphoria). Recent data suggest that some functionally selective, or biased, KOR-targeting agonists might retain the therapeutic effects of KOR activation without inducing undesirable side effects. Nalfurafine, used safely in Japan since 2009 for uremic pruritus, is one such functionally selective KOR-targeting agonist. Here, we quantify the bias of nalfurafine and several other KOR agonists relative to an unbiased reference standard (U50,488) and show that nalfurafine and EOM-salvinorin-B demonstrate marked G protein-signaling bias. While nalfurafine (0.015 mg/kg) and EOM-salvinorin-B (1 mg/kg) produced spinal antinociception equivalent to 5 mg/kg U50,488, only nalfurafine significantly enhanced the supraspinal analgesic effect of 5 mg/kg morphine. In addition, 0.015 mg/kg nalfurafine did not produce significant conditioned place aversion, yet retained the ability to reduce morphine-induced conditioned place preference in C57BL/6J mice. Nalfurafine and EOM-salvinorin-B each produced robust inhibition of both spontaneous and morphine-stimulated locomotor behavior, suggesting a persistence of sedative effects when coadministered with morphine. Taken together, these findings suggest that nalfurafine produces analgesic augmentation, while also reducing opioid-induced reward with less risk of dysphoria. Thus, adjuvant administration of G protein-biased KOR agonists like nalfurafine may be beneficial in enhancing the therapeutic potential of MOR-targeting analgesics, such as morphine.
μ 阿片受体 (MOR) 靶向镇痛药是有效的止痛治疗药物，但因其滥用潜力而臭名昭著。在临床前动物模型中，与 MOR 靶向镇痛药共同给予传统 κ 阿片受体 (KOR) 靶向激动剂可降低奖赏并增强镇痛作用。然而，传统的 KOR 靶向激动剂因引起治疗性不良反应（幻觉、抑郁、焦虑、烦躁）而广为人知。最近的数据表明，一些功能选择性或偏向性的 KOR 靶向激动剂可能保留 KOR 激活的治疗效果，而不引起不良的副作用。纳呋拉啡自 2009 年以来在日本安全用于尿毒症瘙痒，是一种具有这种功能选择性的 KOR 靶向激动剂。在这里，我们定量比较了纳呋拉啡和其他几种 KOR 激动剂相对于无偏参考标准 (U50,488) 的偏向性，并表明纳呋拉啡和 EOM-萨维诺林-B 表现出明显的 G 蛋白信号偏向性。虽然纳呋拉啡（0.015 mg/kg）和 EOM-萨维诺林-B（1 mg/kg）产生的脊髓镇痛作用与 5 mg/kg U50,488 相当，但只有纳呋拉啡显著增强了 5 mg/kg 吗啡的脊髓上镇痛作用。此外，0.015 mg/kg 纳呋拉啡并未产生显著的条件性位置厌恶，但保留了降低 C57BL/6J 小鼠吗啡诱导的条件性位置偏好的能力。纳呋拉啡和 EOM-萨维诺林-B 均对自发性和吗啡刺激的运动行为产生强烈抑制，表明当与吗啡共同给予时，仍存在镇静作用。总之，这些发现表明，纳呋拉啡产生镇痛增强作用，同时降低阿片类药物诱导的奖赏作用，减少烦躁的风险。因此，佐剂给予 G 蛋白偏向性 KOR 激动剂，如纳呋拉啡，可能有益于增强 MOR 靶向镇痛药（如吗啡）的治疗潜力。
