The adverse effects of mu opioid agonists have spurred a renewed interest in using kappa opioid receptor (KOR) agonists as analgesics. KOR agonists also have potential for development as diuretics for the treatment of edema and hypertension. Here, we evaluated the discriminative stimulus, antinociceptive, and diuretic effects of the kappa agonist (±)-trans-U-50488 and its stereoisomers (−)-(1S,2S)-U-50488 or (+)-(1R,2R)-U-50488) alone and in combination with the cannabinoid agonist (−)-CP 55,940. To establish (±)-U-50488 as a discriminative stimulus, rats (n = 12) were trained to discriminate intraperitoneal (i.p.) administration of 5.6 mg/kg of (±)-trans-U-50488 from saline under a fixed-ratio 20 (FR-20) schedule of food reinforcement. Then, antinociception was assessed using two procedures: warm water tail withdrawal and von Frey paw withdrawal. Diuretic effects were assessed in separate rats (n = 6/group). Doses of (±)-U-50488 and (−)-U-50488 that served as discriminative stimuli produced significant increases in urine output, but at lower doses than those that produced antinociception. In contrast, (+)-U-50488 alone had no discriminative stimulus or diuretic effects at the doses tested, but did produce antinociception in the von Frey assay. When three cannabinoids and morphine were tested in the (±)-U-50488 discrimination procedure to determine the similarity of these drugs' discriminative stimulus effects to those for (±)-U-50488, the rank order similarity was (−)-CP 55,940 > (−)-trans-THC > (+)-WIN 55,212–2 ≥ morphine. (−)-CP 55,940 alone (0.056 mg/kg) partially substituted for the discriminative stimulus effects of (±)-U-50488 and produced significant diuretic and antinociceptive effects. (−)-CP 55,940 in combination with (±)-U-50488 also produced a two-fold leftward shift in the discriminative stimulus curve for (±)-U-50488, and near-additive antinociception with (±)-U-50488 and (+)-U-50488. Further, the diuretic effect of (−)-CP 55,940 was enhanced by a dose of (+)-U50488, which itself did not alter urine output. These data together indicate that a combination of cannabinoid and kappa opioid agonists can enhance diuresis, but may have limited potential for serving as opioid-sparing pharmacotherapeutics for treatment of pain.

μ阿片受体激动剂的副作用激发了人们对使用κ阿片受体（KOR）激动剂作为镇痛剂的新兴趣。KOR 激动剂也具有开发作为治疗水肿和高血压的利尿剂的潜力。在这里，我们评估了 kappa 激动剂 (±)-trans-U-50488 及其立体异构体 (-)-(1 S ,2 S )-U-50488 或 (+)-( 1 R ,2 R )-U-50488) 单独和与大麻素激动剂 (-)-CP 55,940 联合使用。为了建立 (±)-U-50488 作为区分刺激，大鼠 ( n = 12) 接受了训练，以在固定比率 20 (FR-20) 的食物强化计划下区分腹膜内 (ip) 给药 5.6 mg/kg (±)-trans-U-50488 和盐水。然后，使用两种程序评估镇痛作用：温水缩尾和冯弗雷缩爪。在不同的大鼠中评估利尿作用（n = 6/组）。(±)-U-50488 和 (-)-U-50488 的剂量作为区分刺激产生显着增加的尿量，但剂量低于产生镇痛作用的剂量。相比之下，单独的 (+)-U-50488 在测试的剂量下没有区分刺激或利尿作用，但在 von Frey 试验中确实产生了镇痛作用。当在 (±)-U-50488 鉴别程序中测试三种大麻素和吗啡以确定这些药物的鉴别刺激效应与 (±)-U-50488 的相似性时，排序相似性为 (-)-CP 55,940 > (−)-trans-THC > (+)-WIN 55,212–2 ≥ 吗啡。(−)-CP 55,940 (0.056 mg/kg) 部分替代了 (±)-U-50488 的辨别刺激作用，并产生显着的利尿和镇痛作用。(-)-CP 55, 940 与 (±)-U-50488 的组合也使 (±)-U-50488 的辨别刺激曲线向左移动了两倍，以及与 (±)-U-50488 和 (+) 的近加性镇痛作用-U-50488。此外，(-)-CP 55,940 的利尿作用因 (+)-U50488 的剂量而增强，其本身不会改变尿量。这些数据共同表明大麻素和κ阿片受体激动剂的组合可以增强利尿作用，但作为节省阿片类药物治疗疼痛的药物的潜力可能有限。