Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC, USA.
Neuropsychopharmacology. 2022 Nov;47(12):2132-2139. doi: 10.1038/s41386-022-01393-3. Epub 2022 Jul 29.
The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However, methadone has undesirable effects that limit its clinical efficacy. Intermediate efficacy MOR agonists may treat OUD with fewer undesirable effects. We compared the effects of methadone with the intermediate efficacy MOR agonist TRV130 (oliceridine) on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats. Male rats (n = 20) were trained under a fentanyl-vs.-food choice procedure. Rats were then provided extended fentanyl (3.2 µg/kg/infusion) access (6 p.m.-6 a.m.) for 10 days to produce opioid dependence/withdrawal. Rats were treated with vehicle (n = 7), TRV130 (3.2 mg/kg; n = 8), or methadone (3.2 mg/kg; n = 5) three times per day after each extended-access session (8:30 a.m., 11 a.m., 1:30 p.m.). Withdrawal sign scoring (1:55 p.m.) and choice tests (2-4 p.m.) were conducted daily. Vehicle, TRV130, and methadone effects on fentanyl choice were redetermined in post-opioid-dependent rats. Vehicle-, TRV130-, and methadone-treated rats had similar fentanyl intakes during extended access. Vehicle-treated rats exhibited increased withdrawal signs and decreased bodyweights. Both methadone and TRV130 decreased these withdrawal signs. TRV130 was less effective than methadone to decrease fentanyl choice and increase food choice in opioid-dependent rats. Neither methadone nor TRV130 decreased fentanyl choice in post-opioid-dependent rats. Results suggest that higher MOR activation is required to reduce fentanyl choice than withdrawal signs in fentanyl-dependent rats. Additionally, given that TRV130 did not precipitate withdrawal in opioid-dependent rats, intermediate efficacy MOR agonists like TRV130 may facilitate the transition of patients with OUD from methadone to lower efficacy treatments like buprenorphine.
高效能μ-阿片受体（MOR）激动剂美沙酮是一种专门用于阿片类药物依赖患者的有效的阿片类药物使用障碍（OUD）药物。然而，美沙酮具有不良影响，限制了其临床疗效。中等效能 MOR 激动剂可能会以较少的不良影响治疗 OUD。我们比较了美沙酮与中等效能 MOR 激动剂 TRV130（奥列西定）对阿片类药物依赖和阿片类药物依赖后大鼠芬太尼与食物选择和躯体戒断症状的影响。雄性大鼠（n=20）在芬太尼与食物选择程序下接受训练。然后，大鼠给予延长的芬太尼（3.2µg/kg/输注）（下午 6 点至上午 6 点）10 天，以产生阿片类药物依赖/戒断。大鼠给予载体（n=7）、TRV130（3.2mg/kg；n=8）或美沙酮（3.2mg/kg；n=5），每天在每个延长访问会话后三次（上午 8:30、上午 11 点、下午 1:30）。下午 1:55 进行戒断症状评分（下午 1:55）和选择测试（下午 2-4 点）。在阿片类药物依赖后大鼠中重新确定了载体、TRV130 和美沙酮对芬太尼选择的影响。载体、TRV130 和美沙酮处理的大鼠在延长的访问期间具有相似的芬太尼摄入量。载体处理的大鼠表现出戒断症状增加和体重减轻。美沙酮和 TRV130 均降低了这些戒断症状。TRV130 降低芬太尼选择和增加阿片类药物依赖大鼠食物选择的效果不如美沙酮。美沙酮和 TRV130 均未降低阿片类药物依赖后大鼠对芬太尼的选择。结果表明，与芬太尼依赖大鼠的戒断症状相比，降低芬太尼选择需要更高的 MOR 激活。此外，鉴于 TRV130 未在阿片类药物依赖大鼠中引发戒断，像 TRV130 这样的中等效能 MOR 激动剂可能有助于 OUD 患者从美沙酮过渡到低效能治疗，如丁丙诺啡。
