Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
Departments of Molecular Medicine and Chemistry, The Scripps Research Institute, Jupiter, FL, USA.
Neuropharmacology. 2021 Mar 1;185:108439. doi: 10.1016/j.neuropharm.2020.108439. Epub 2020 Dec 17.
The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPγS 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.
μ 阿片受体选择性激动剂 SR-17018 在细胞检测中优先激活 GTPγS 结合，而不是招募β-arrestin2，从而表现出信号偏向。在小鼠中，SR-17018 刺激脑干中的 GTPγS 结合，并产生与吗啡相似效力的镇痛作用。然而，它引起的呼吸抑制要少得多，并且在反复给予时，小鼠在热板试验中不会产生镇痛耐受。在此，我们评估了 SR-17018、羟考酮和吗啡在其他疼痛相关行为模型中的急性和重复给药的效果。在小鼠温水尾巴浸入试验中，评估脊髓对热伤害感受的反射，反复给予 SR-17018 会产生与吗啡和羟考酮相似的耐受。SR-17018 在重复给予时在福尔马林诱导的炎症性疼痛模型中保持疗效，而羟考酮则没有。在化疗诱导的神经病变疼痛模型中，SR-17018 比吗啡或羟考酮更有效且更有效，而且，在重复给予 SR-17018 时，这种疗效仍然存在。这些发现表明，除了尾巴拍打试验外，SR-17018 在几种疼痛模型的慢性治疗中保持疗效。
