Effects of Smoking on Opioid Receptor Binding: a PET Imaging Study

吸烟对阿片受体结合的影响：PET 成像研究

• 批准号: 8553292
• 负责人: Stephen Heishman
• 金额: $ 21.9万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553292
• 关键词: Acute; Adult; Awareness; Binding; Cells; Chronic; Cigarette; Dopamine; Dose; Endorphins; Enrollment; Genetic Polymorphism; Health; Human; Measures; Mediating; Morbidity - disease rate; Mus; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleus Accumbens; Opioid; Opioid Receptor Binding; Outcome Measure; Patient Self-Report; Pharmaceutical Preparations; Positron-Emission Tomography; Reporting; Secondary to; Smoker; Smoking; System; Testing; Time; Tobacco smoking; Up-Regulation; drug of abuse; endogenous opioids; improved; mortality; mu opioid receptors; non-smoker; preclinical study; therapy development

Tobacco smoking is the leading preventable cause of morbidity and mortality in the world, yet despite decades of public awareness campaigns on the adverse health consequences of smoking, 21.5% of adults in the U.S. are daily smokers. The reinforcing effects of nicotine are mediated in part via its effects on α4β2 nicotinic acetylcholine receptors, which result in activation of dopamine (DA) cells and increased release of DA in the nucleus accumbens (NAc). In fact, the ability of most addictive drugs to increase DA in the NAc is believed to be a common mechanism through which drugs of abuse exert their reinforcing effects. However, preclinical studies have shown that nicotine also results in release of endogenous opioids, which is also likely to contribute to its reinforcing effects because nicotine is not reinforcing in mice that do not express mu-opioid receptors. Thus, a more complete understanding of the acute and chronic effects of nicotine on the endogenous opioid system in humans might provide improved strategies for medication development for the treatment of nicotine dependence. In this study, we propose to investigate whether nicotine at the dose delivered through a cigarette (1-2 mg) will increase the release of endogenous opioids. We will also determine whether smokers have adaptations in the opioid system compared with nonsmokers. We will test 20 smokers and 20 nonsmokers. Outcome measures include: 1) displacement of 11Ccarfentanil binding, secondary to the release of endorphins by nicotine; 2) upregulation of 11Ccarfentanil specific binding in smokers compared with nonsmokers; 3) 11Ccarfentanil specific binding as a function of the mu-opioid receptor A118G polymorphism; and 4) correlation between self-report measures of nicotine effect and 11Ccarfentanil binding profile. During the past year, we have initiated the study and completed testing of 6 subjects. Because study enrollment is ongoing, we have no findings to report at this time.

吸烟是世界上发病率和死亡率的主要预防原因，尽管数十年来对吸烟的不良健康后果进行了数十年的公众意识运动，但美国有21.5％的成年人是每日吸烟者。尼古丁的增强作用部分是通过其对α4β2烟碱乙酰胆碱受体的作用的部分介导的，这会导致多巴胺（DA）细胞的激活和Accumbens（NAC）中DA释放的增加。 实际上，大多数成瘾性药物在NAC中增加DA的能力被认为是一种常见的机制，滥用药物会产生增强作用。 然而，临床前研究表明，尼古丁也会导致内源性阿片类药物的释放，这也可能有助于其增强作用，因为尼古丁在不表达MU-阿片类受体的小鼠中没有加强。因此，对尼古丁对人类内源性阿片类药物系统的急性和慢性作用的急性和慢性作用的更全面了解可能会为治疗尼古丁依赖性的药物开发提供改进的策略。 在这项研究中，我们建议研究通过香烟（1-2 mg）剂量下的尼古丁是否会增加内源性阿片类药物的释放。 我们还将确定吸烟者与非吸烟者相比是否在阿片类药物系统中具有适应性。我们将测试20名吸烟者和20名非吸烟者。 结果指标包括：1）nigotine释放内啡肽的11 ccarfentanil结合的位移； 2）与非吸烟者相比，吸烟者的11carfentanil特异性结合上调； 3）11 ccarfentanil特异性结合是mu阿片受体A118G多态性的函数； 4）尼古丁效应的自我报告测量与11carfentanil结合曲线之间的相关性。 在过去的一年中，我们启动了研究并完成了6名受试者的测试。 由于研究入学率正在进行中，因此目前我们没有发现的发现。