Section for Drug Abuse Research, Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway.
School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
Addict Biol. 2020 Mar;25(2):e12727. doi: 10.1111/adb.12727. Epub 2019 Feb 20.
We have previously demonstrated that heroin's first metabolite, 6-acetylmorphine (6-AM), is an important mediator of heroin's acute effects. However, the significance of 6-AM to the rewarding properties of heroin still remains unknown. The present study therefore aimed to examine the contribution of 6-AM to heroin-induced reward and locomotor sensitization. Mice were tested for conditioned place preference (CPP) induced by equimolar doses of heroin or 6-AM (1.25-5 μmol/kg). Psychomotor activity was recorded during the CPP conditioning sessions for assessment of drug-induced locomotor sensitization. The contribution of 6-AM to heroin reward and locomotor sensitization was further examined by pretreating mice with a 6-AM specific antibody (anti-6-AM mAb) 24 hours prior to the CPP procedure. Both heroin and 6-AM induced CPP in mice, but heroin generated twice as high CPP scores compared with 6-AM. Locomotor sensitization was expressed after repeated exposure to 2.5 and 5 μmol/kg heroin or 6-AM, but not after 1.25 μmol/kg, and we found no correlation between the expression of CPP and the magnitude of locomotor sensitization for either opioid. Pretreatment with anti-6-AM mAb suppressed both heroin-induced and 6-AM-induced CPP and locomotor sensitization. These findings provide evidence that 6-AM is essential for the rewarding and sensitizing properties of heroin; however, heroin caused stronger reward compared with 6-AM. This may be explained by the higher lipophilicity of heroin, providing more efficient drug transfer to the brain, ensuring rapid increase in the brain 6-AM concentration.
我们之前已经证明，海洛因的第一个代谢物 6-乙酰吗啡（6-AM）是海洛因急性作用的重要介质。然而，6-AM 对海洛因奖赏特性的重要性尚不清楚。因此，本研究旨在研究 6-AM 对海洛因诱导的奖赏和运动敏化的贡献。通过等摩尔剂量的海洛因或 6-AM（1.25-5 μmol/kg）测试小鼠的条件性位置偏爱（CPP）。在 CPP Conditioning 期间记录精神运动活动，以评估药物诱导的运动敏化作用。通过在 CPP 程序之前 24 小时用 6-AM 特异性抗体（抗-6-AM mAb）预处理小鼠，进一步研究了 6-AM 对海洛因奖赏和运动敏化的贡献。海洛因和 6-AM 均可诱导小鼠 CPP，但海洛因生成的 CPP 评分是 6-AM 的两倍。反复暴露于 2.5 和 5 μmol/kg 海洛因或 6-AM 后，出现运动敏化，但在 1.25 μmol/kg 时没有出现，我们没有发现 CPP 表达与任何阿片类药物的运动敏化幅度之间存在相关性。抗-6-AM mAb 预处理抑制了海洛因诱导和 6-AM 诱导的 CPP 和运动敏化。这些发现提供了证据，表明 6-AM 是海洛因奖赏和敏化特性的必要条件；然而，海洛因引起的奖赏作用强于 6-AM。这可能是由于海洛因的脂溶性更高，能够更有效地将药物转移到大脑中，确保大脑 6-AM 浓度迅速增加。
