The Scripps Research Institute, 10550 North Torrey Pines Road, SR-107, La Jolla, CA, 92037, USA.
The Scripps Research Institute, 10550 North Torrey Pines Road, SR-107, La Jolla, CA, 92037, USA.
Neuropharmacology. 2023 Nov 15;239:109685. doi: 10.1016/j.neuropharm.2023.109685. Epub 2023 Aug 12.
Chronic opioid use disturbs circadian rhythm and sleep, encouraging opioid use and relapse. The orexin (OX) system is recruited by opioids and regulates physiological processes including sleep. Dual OX receptor antagonists (DORAs), developed for insomnia treatment, may relieve withdrawal-associated sleep disturbances. This study investigated whether DORA-12, a recently developed DORA, reduces physiological activity disturbances during oxycodone abstinence and consequently prevents oxycodone-seeking behavior. Male and female Wistar rats were trained to intravenously self-administer oxycodone (0.15 mg/kg, 21 sessions; 8 h/session) in the presence of a contextual/discriminative stimulus (S). The rats were subsequently housed individually (22 h/day) to monitor activity, food and water intake. They received DORA-12 (0-30 mg/kg, p.o.) after undergoing daily 1-h extinction training (14 days). After extinction, the rats were tested for oxycodone-seeking behavior elicited by the S. Hypothalamus sections were processed to assess oxycodone- or DORA-12-associated changes to the OX cell number. In males, oxycodone-associated increases in activity during the light-phase, reinstatement, and decreases in the number of OX cells observed in the vehicle-treated group were not observed with DORA-12-treatment. Oxycodone-associated increases in light-phase food and water intake were not observed by day 14 of 3 mg/kg DORA-12-treatment and dark-phase water intake was increased across treatment days. In females, OX cell number was unaffected by oxycodone or DORA-12. Three and 30 mg/kg DORA-12 increased females' day 7 dark-phase activity and decreased reinstatement. Thirty mg/kg DORA-12 reduced oxycodone-associated increases in light-phase food and water intake. The results suggest that DORA-12 improves oxycodone-induced disruptions to physiological activities and reduces relapse.
慢性阿片类药物使用会扰乱昼夜节律和睡眠，从而鼓励阿片类药物的使用和复发。孤啡肽（OX）系统受阿片类药物的招募，并调节包括睡眠在内的生理过程。双孤啡肽受体拮抗剂（DORAs）是为治疗失眠而开发的，可能缓解戒断相关的睡眠障碍。本研究调查了最近开发的 DORA-12 是否能减少氧可酮戒断期间生理活动的紊乱，并因此防止氧可酮觅药行为。雄性和雌性 Wistar 大鼠接受训练，通过静脉内自我给予氧可酮（0.15mg/kg，21 次；8 小时/次），同时存在一个情境/辨别刺激（S）。然后，大鼠被单独饲养（22 小时/天），以监测活动、食物和水的摄入。在经历每天 1 小时的消退训练（14 天）后，它们接受 DORA-12（0-30mg/kg，口服）治疗。消退后，用 S 测试大鼠的氧可酮觅药行为。处理下丘脑切片，以评估氧可酮或 DORA-12 与 OX 细胞数量变化相关的情况。在雄性中，与 DORA-12 治疗相关的观察到的药物相关活动增加、复吸，以及在对照组中观察到的 OX 细胞数量减少在 DORA-12 治疗组中没有观察到。在第 3mg/kg DORA-12 治疗的第 14 天，未观察到与氧可酮相关的光期食物和水摄入增加，而整个治疗过程中暗期水摄入增加。在雌性中，OX 细胞数量不受氧可酮或 DORA-12 的影响。3mg/kg 和 30mg/kg DORA-12 增加了雌性第 7 天的暗期活动，并减少了复吸。30mg/kg DORA-12 减少了与氧可酮相关的光期食物和水摄入增加。结果表明，DORA-12 改善了氧可酮引起的生理活动紊乱，并减少了复发。
