Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):146-53. doi: 10.1016/j.pnpbp.2010.10.007. Epub 2010 Oct 20.
There has long been an interest in examining the involvement of opioid neurotransmission in nicotine rewarding process and addiction to nicotine. Over the past 3 decades, however, clinical effort to test the effectiveness of nonselective opioid antagonists (mainly naloxone and naltrexone) for smoking cessation has yielded equivocal results. In light of the fact that there are three distinctive types of receptors mediating actions of the endogenous opioid peptides, this study, using a rat model of nicotine self-administration, examined involvement of different opioid receptors in the reinforcement of nicotine by selective blockade of the μ1, the δ, and the κ opioid receptors. Male Sprague-Dawley rats were trained in daily 1h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. After establishment of stable nicotine self-administration behavior, the effects of the opioid antagonists were tested. Separate groups of rats were used to test the effects of naloxanazine (selective for μ1 receptors, 0, 5 and 15 mg/kg), naltrindole (selective for δ receptors, 0, 0.5 and 5mg/kg), and 5'-guanidinonaltrindole (GNTI, selective for κ receptors, 0, 0.25 and 1mg/kg). In each individual drug group, the 3 drug doses were tested by using a within-subject and Latin-Square design. The effects of these antagonists on food self-administering behavior were also examined in the same rats in each respective drug group after retrained for food self-administration. Pretreatment with naloxonazine, but not naltrindole or GNTI, significantly reduced responses on the active lever and correspondingly the number of nicotine infusions. None of these antagonists changed lever-pressing behavior for food reinforcement. These results indicate that activation of the opioid μ1, but not the δ or the κ, receptors is required for the reinforcement of nicotine and suggest that opioid neurotransmission via the μ1 receptors would be a promising target for the development of opioid ligands for smoking cessation.
长期以来，人们一直对研究阿片类神经递质在尼古丁奖赏过程和尼古丁成瘾中的作用感兴趣。然而，在过去的 30 年中，临床努力测试非选择性阿片拮抗剂（主要是纳洛酮和纳曲酮）戒烟的效果产生了不确定的结果。鉴于介导内源性阿片肽作用的有三种不同类型的受体，本研究使用尼古丁自我给药的大鼠模型，通过选择性阻断μ1、δ和κ阿片受体，研究了不同阿片受体在尼古丁强化中的作用。雄性 Sprague-Dawley 大鼠在每天 1 小时的静脉内自我给药尼古丁（0.03mg/kg/ 输注）的固定比例 5 时间表中接受训练。在建立稳定的尼古丁自我给药行为后，测试了阿片拮抗剂的作用。使用单独的大鼠组来测试纳洛那嗪（选择性作用于μ1 受体，0、5 和 15mg/kg）、纳曲吲哚（选择性作用于δ 受体，0、0.5 和 5mg/kg）和 5'-胍基纳曲吲哚（GNTI，选择性作用于κ 受体，0、0.25 和 1mg/kg）的作用。在每个单独的药物组中，通过使用个体内和拉丁方设计测试了 3 种药物剂量。在每个相应的药物组中，在重新训练食物自我给药后，还检查了这些拮抗剂对食物自我给药行为的影响。纳洛那嗪预处理，但不是纳曲吲哚或 GNTI，显著减少了主动杆上的反应，相应地减少了尼古丁输注的次数。这些拮抗剂都没有改变食物强化的杆按压行为。这些结果表明，阿片类μ1 受体的激活，但不是 δ 或 κ 受体的激活，是尼古丁强化所必需的，这表明通过μ1 受体的阿片类神经传递将是开发用于戒烟的阿片类配体的有前途的目标。
