Department of Family and Community Medicine, University of Kentucky.
Behavioral Pharmacology Research Unit, Johns Hopkins University.
Exp Clin Psychopharmacol. 2021 Dec;29(6):636-649. doi: 10.1037/pha0000375. Epub 2020 Apr 16.
Opioid use disorder (OUD) is a significant health problem, and understanding mechanisms of various aspects of OUD including drug use and withdrawal is important. Preclinical models provide an ideal opportunity to evaluate mechanisms underlying opioid withdrawal. Current models are limited by their reliance upon forced opioid administration, focus on the acute (and not protracted) syndrome, and exclusion of females. In this study, male and female rats self-administered heroin (maintenance dose of 12.5 μg/kg/infusion) and opioid withdrawal after abrupt discontinuation was measured. In Phase 1, acute withdrawal symptoms were rated in male and female rats at 0, 16, 48, and 72 hr after the last self-administration session. Total somatic signs increased until 48 hr (predominantly in females), and heroin intake positively correlated with total somatic signs at the 48 and 72 hr timepoints. Measures of hyperactivity and anxiety-like behavior increased by 16 and 48 hr, respectively. In Phase 2, symptoms were assessed at baseline, acute, and protracted (168 and 312 hr after self-administration) timepoints in a subset of male and female rats from Phase 1. The total number of somatic signs did not differ across timepoints, though females displayed significantly higher body temperature at all timepoints compared with males, indicating sex-specific protracted withdrawal symptomatology. These data provide a thorough characterization of rodent opioid withdrawal symptomatology after self-administration and abrupt discontinuation that serve as a foundation for future studies designed to mimic the human experience, and demonstrate the importance of characterizing acute and protracted withdrawal with sex-specificity in preclinical models of opioid self-administration. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
阿片类使用障碍（OUD）是一个严重的健康问题，了解包括药物使用和戒断在内的 OUD 各个方面的机制非常重要。临床前模型为评估阿片戒断的潜在机制提供了一个理想的机会。目前的模型受到其对强制阿片类药物给药的依赖、对急性（而非迁延性）综合征的关注以及对雌性动物的排除的限制。在这项研究中，雄性和雌性大鼠自行注射海洛因（维持剂量为 12.5 μg/kg/输注），并在突然停药后测量阿片戒断。在第 1 阶段，在最后一次自我给药后 0、16、48 和 72 小时，对雄性和雌性大鼠的急性戒断症状进行了评分。总躯体症状一直增加到 48 小时（主要在雌性中），并且海洛因摄入量与 48 和 72 小时时的总躯体症状呈正相关。多动和焦虑样行为的测量分别在 16 和 48 小时增加。在第 2 阶段，在第 1 阶段的一部分雄性和雌性大鼠中，在基线、急性和迁延（自给药后 168 和 312 小时）时间点评估了症状。尽管雌性在所有时间点的体温均显著高于雄性，但总躯体症状的数量在各时间点均无差异，表明存在性别特异性迁延性戒断症状。这些数据提供了对自行给药和突然停药后啮齿动物阿片戒断症状的全面描述，为未来旨在模拟人类体验的研究奠定了基础，并表明在阿片类药物自我给药的临床前模型中，对急性和迁延性戒断进行性别特异性描述的重要性。（PsycInfo 数据库记录（c）2021 APA，保留所有权利）。
