Abstract：
Maintenance therapy with buprenorphine and methadone is the gold standard pharmacological treatment for opioid use disorder (OUD). Despite these compounds demonstrating substantial efficacy, a significant number of patients do not show optimal therapeutic responses. The abuse liability of these medications is also a concern. Here we used rats to explore the therapeutic potential of the new long-acting pan-opioid agonist Cebranopadol in OUD. We tested the effect of cebranopadol on heroin self-administration and yohimbine-induced reinstatement of heroin seeking. In addition, we evaluated the abuse liability potential of cebranopadol in comparison to that of heroin under fixed ratio 1 (FR1) and progressive ratio (PR) operant self-administration contingencies. Oral administration of cebranopadol (0, 25, 50μg/kg) significantly attenuated drug self-administration independent of heroin dose (1, 7, 20, 60μg/inf). Cebranopadol also reduced the break point for heroin (20 μg/inf). Finally, pretreatment with cebranopadol significantly attenuated yohimbine-induced reinstatement of drug seeking. In abuse liability experiments under FR1 contingency, rats maintained responding for heroin (1, 7, 20, 60μg/inf) to a larger extent than cebranopadol (0.03, 0.1, 0.3, 1.0, 6.0μg/inf). Under PR contingency, heroin maintained responding at high levels at all except the lowest dose, while the break point (BP) for cebranopadol did not differ from that of saline. Together, these data indicate that cebranopadol is highly efficacious in attenuating opioid self-administration and stress-induced reinstatement, while having limited abuse liability properties. Overall, the data suggest clinical potential of this compound for OUD treatment.
摘要：
丁丙诺啡和美沙酮的维持治疗是阿片类药物使用障碍（OUD）的黄金标准药物治疗。尽管这些化合物显示出实质性的功效，相当数量的患者未显示最佳治疗反应.这些药物的滥用责任也令人担忧。在这里，我们使用大鼠来探索新型长效泛阿片激动剂Cebranopadol在OUD中的治疗潜力。我们测试了cebranopadol对海洛因自我给药和育亨宾诱导的海洛因寻求恢复的影响。此外,我们评估了在固定比率1(FR1)和累进比率(PR)的操作性自我给药意外情况下,与海洛因相比,西布拉诺帕多的滥用责任可能性.口服头孢拉帕多（0、25、50μg/kg）可显着减弱药物的自我给药，而与海洛因剂量（1、7、20、60μg/inf）无关。Cebranopadol还降低了海洛因的断点（20μg/inf）。最后,用cebranopadol预处理可显着减弱育亨宾诱导的药物寻求恢复。在FR1应急条件下的滥用责任实验中，大鼠对海洛因（1、7、20、60μg/inf）的反应比西布拉帕多（0.03、0.1、0.3、1.0、6.0μg/inf）更大。根据公关应急，除最低剂量外，海洛因均保持高水平反应，而西班帕多的断裂点（BP）与盐水没有差异。一起,这些数据表明，西布拉帕多在减弱阿片类药物的自我给药和应激诱导的恢复方面非常有效，同时具有有限的滥用责任属性。总的来说,数据提示该化合物用于OUD治疗的临床潜力.
