Department of Neurology and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, 170 Manning Dr., CB 7025, Chapel Hill, NC 27599-7025, USA.
Psychopharmacology (Berl). 2012 Mar;220(1):215-24. doi: 10.1007/s00213-011-2469-z. Epub 2011 Sep 10.
The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists.
This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method.
Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline.
Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX.
The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.
阿片类药物的滥用潜力可能与其强化和奖赏作用有关，而神经激肽-1 受体 (NK1R) 拮抗剂可能会减弱这些作用。
本研究旨在使用颅内自我刺激方法测量阿片类药物和 NK1R 阻断对吗啡增强脑刺激奖赏 (BSR) 的影响。
成年雄性 C57BL/6J 小鼠（n = 15）植入单极刺激电极于外侧下丘脑，并接受不同频率奖赏性电刺激的训练。在腹腔注射生理盐水、吗啡（1.0-17.0 mg/kg）或 NK1R 拮抗剂 L-733,060（1.0-17.0 mg/kg）和 L-703,606（1.0-17.0 mg/kg）前后，测定 BSR 阈值（θ(0)）和最大反应率（MAX）。在吗啡拮抗实验中，纳曲酮（0.1-1.0 mg/kg）或 10.0 mg/kg L-733,060 或 L-703,606 在给予吗啡（1.0-10.0 mg/kg）或生理盐水前 15 分钟给药。
吗啡剂量依赖性地降低了 θ(0)（最大效应为基线的 62%）并改变了 MAX，与生理盐水相比。L-703,606 和 L-733,060 改变了 θ(0)；10.0 mg/kg L-733,060 和 L-703,606 不影响 θ(0)或 MAX，减弱了 3.0 和 10.0 mg/kg 吗啡的作用，而 1.0 和 0.3 mg/kg 纳曲酮阻断了 10.0 mg/kg 吗啡的作用。纳曲酮在给予生理盐水之前不影响 θ(0)或 MAX。
吗啡引起的 θ(0)降低反映了其奖赏作用，而 NK1R 和阿片受体阻断可减弱其作用。这些结果表明，在阿片类药物激活边缘奖赏系统时，P 物质信号的重要性。
