The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPS binding over beta-arrestin2 recruitment in cellular assays. In mice, SR-17018 stimulates GTPgammaS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.

中文翻译：

---

吗啡，羟考酮和偏向性MOR激动剂SR-17018在小鼠疼痛模型中的耐受性和功效比较。

在细胞分析中，μ阿片类受体选择性激动剂SR-17018比β-arrestin2募集优先激活GTPS结合。在小鼠中，SR-17018刺激脑干中的GTPgammaS结合，并产生与吗啡相似的镇痛作用。但是，它产生的呼吸抑制作用要少得多，并且在重复给药后，小鼠在热板试验中不会产生抗伤害感受的能力。在本文中，我们评估了SR-17018，羟考酮和吗啡的急性和反复给药在疼痛相关行为的其他模型中的作用。在小鼠温水尾部浸没测定中，对脊髓对热伤害感受的反射进行评估，重复施用SR-17018会产生耐受性，吗啡和羟考酮也是如此。重复给药后，SR-17018在福尔马林诱发的炎性疼痛模型中保持功效，羟考酮则没有。在化学疗法诱导的神经病性疼痛模型中，SR-17018比吗啡或羟考酮更有效，更有效，而且，在重复给药SR-17018后，这种功效得以保持。这些发现表明，除甩尾试验外，SR-17018在多种疼痛模型的慢性治疗中均保持疗效。