Sharafshah Alireza, Lewandrowski Kai-Uwe, Elman Igor, Baron David, Thanos Panayotis K, Hanna Colin, Gold Mark S, Badgaiyan Rajendra D, Cadet Jean Lud, Modestino Edward J, Braverman Eric, Dennen Catherine A, Makale Milan, Sunder Keerthy, Murphy Kevin T, Bowirrat Abdalla, Pinhasov Albert, Gondre-Lewis Marjorie, Gardner Eliot, Sipple Daniel, Jafari Nicole, Zeine Foojan, Khalsa Jag, Fiorelli Rossano Kepler Alvim, Blum Kenneth
Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
Department of Orthopaedics, Fundación Universitaria Sanitas Bogotá D.C. Colombia.
Curr Pharm Biotechnol. 2025 Apr 16. doi: 10.2174/0113892010353450250408114725.
Overdose involving opioids is the black heart of the addiction crisis. "Pre-addiction," as an encouraging concept by NIDA and NIAAA, seems best captured with the construct of dopamine dysregulation. Referring to the abundant publications on "Reward Deficiency Syndrome" (RDS), Genetic Addiction Risk Score (GARS) test, RDSQ29, and KB220, Pre-addiction can be referred to as "reward dysregulation" as a suitable suggestion. The hypothesis is that the true phenotype is RDS, and other behavioral disorders are endophenotypes where the genetic variants play important roles, specifically in the Brain Reward Cascade (BRC).
This study tested the pharmacogenomics of the GARS panel by a multi-model in silico investigation in four layers: 1) Protein-Protein Interactions (PPIs); 2) Gene Regulatory Networks (GRNs); 3) Disease, drugs and chemicals (DDCs); and 4) Gene Coexpression Networks (GCNs).
All in silico findings were combined in an Enrichment Analysis for 59 refined genes, which represented highly significant associations of dopamine pathways in the BRC and supported our hypothesis.
This paper provides scientific evidence for the importance of incorporating GARS as a predictive test to identify Pre-addiction, introduce unique therapeutic targets assisting in the treatment of pain, drug dosing of prescription pharmaceuticals, and identify the risk for subsequent addiction early in -life.
阿片类药物过量是成瘾危机的核心问题。美国国立药物滥用研究所（NIDA）和美国国立酒精滥用与酒精中毒研究所（NIAAA）提出的“成瘾前状态”这一令人鼓舞的概念，似乎可以用多巴胺调节异常的概念来最好地描述。参考大量关于“奖励缺乏综合征”（RDS）、遗传成瘾风险评分（GARS）测试、RDSQ29和KB220的出版物，“成瘾前状态”可被称为“奖励调节异常”，这是一个合适的建议。假设真正的表型是RDS，而其他行为障碍是内表型，其中基因变异起着重要作用，特别是在脑奖励级联反应（BRC）中。
本研究通过多模型计算机模拟研究，在四个层面测试了GARS检测板的药物基因组学：1）蛋白质-蛋白质相互作用（PPI）；2）基因调控网络（GRN）；3）疾病、药物和化学物质（DDC）；4）基因共表达网络（GCN）。
所有计算机模拟研究结果在一项针对59个精细基因的富集分析中进行了整合，这些基因代表了BRC中多巴胺通路的高度显著关联，并支持了我们的假设。
本文为将GARS作为一种预测性检测以识别成瘾前状态、引入独特的治疗靶点辅助疼痛治疗、确定处方药的给药剂量以及在生命早期识别后续成瘾风险的重要性提供了科学证据。
