评估阿片类药物和多巴胺相关基因多态性对羟考酮滥用倾向的贡献。
Assessing the contribution of opioid- and dopamine-related genetic polymorphisms to the abuse liability of oxycodone.
机构信息
Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA.
Translational Research Training Program in Addiction, City College of New York, 160 Convent Avenue, New York, NY 10031, USA; Sophie Davis School of Biomedical Education, 160 Convent Avenue, New York, NY 10032, USA.
出版信息
Pharmacol Biochem Behav. 2019 Nov;186:172778. doi: 10.1016/j.pbb.2019.172778. Epub 2019 Sep 4.
BACKGROUND
Attempts to identify opioid users at increased risk of escalating to opioid use disorder have had limited success. Data from a variety of sources suggest that genetic variation may mediate the subjective response to opioid drugs, and therefore contribute to their abuse potential. The goal of the current study was to observe the relationship between select genetic polymorphisms and the subjective effects of oxycodone under controlled clinical laboratory conditions.
METHODS
Non-dependent, volunteers with some history of prescription opioid exposure (N = 36) provided a blood sample for analyses of variations in the genes that encode for the μ-, κ- and δ-opioid receptors, and the dopamine metabolizing enzyme, catechol-O-methyltransferase (COMT). Participants then completed a single laboratory test session to evaluate the subjective and analgesic effects of oral oxycodone (0, 10, and 20 mg, cumulative dose = 30 mg).
RESULTS
Oxycodone produced typical μ-opioid receptor agonist effects, such as miosis, and decreased pain perception. Oxycodone also produced dose-dependent increases in positive subjective responses such as: drug "Liking" and "Good Effect." Genetic variants in the μ- (rs6848893) and δ-opioid receptor (rs581111) influenced the responses to oxycodone administration. Additionally, self-reported "Stimulated" effects of oxycodone varied significantly as a function of COMT rs4680 genotype.
DISCUSSION
The current study shows that the euphoric and stimulating effects of oxycodone can vary as a function of genetic variation. Though the relationship between the stimulating effects of opioids and their abuse liability is not well established, we know that the ability of opioids to provide intense feelings of pleasure is a significant motivator for continued use. If replicated, specific genetic variants may be useful in predicting who is at increased risk of developing maladaptive patterns of use following medical exposure to opioid analgesics.
背景
识别阿片类药物使用者中存在阿片类药物使用障碍风险增加的尝试取得的成功有限。来自各种来源的数据表明，遗传变异可能调节阿片类药物的主观反应，因此可能对其滥用潜力产生影响。本研究的目的是观察在受控临床实验室条件下，选择基因多态性与羟考酮的主观作用之间的关系。
方法
非依赖性、有一定处方阿片类药物暴露史的志愿者（N=36）提供血液样本，用于分析编码μ-、κ-和δ-阿片受体以及多巴胺代谢酶儿茶酚-O-甲基转移酶（COMT）的基因的变异。然后，参与者完成单次实验室测试，以评估口服羟考酮（0、10 和 20mg，累积剂量=30mg）的主观和镇痛作用。
结果
羟考酮产生了典型的μ-阿片受体激动剂作用，如瞳孔缩小和疼痛感知降低。羟考酮还导致阳性主观反应（如“喜欢”和“良好效果”）呈剂量依赖性增加。μ-（rs6848893）和 δ-阿片受体（rs581111）的基因变异影响了羟考酮给药的反应。此外，羟考酮的自我报告“兴奋”作用的变异与 COMT rs4680 基因型显著相关。
讨论
本研究表明，羟考酮的欣快和刺激作用可以根据遗传变异而变化。虽然阿片类药物的兴奋作用与滥用倾向之间的关系尚未得到充分确立，但我们知道阿片类药物提供强烈愉悦感的能力是继续使用的重要动机。如果得到复制，特定的遗传变异可能有助于预测在医学暴露于阿片类镇痛药后，谁有发展适应不良使用模式的风险增加。
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