Perinatal fentanyl exposure drives enduring addiction risk and central amygdala gene dysregulation

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-06-27 DOI:10.1016/j.neuropharm.2025.110581

Courtney P. Wood , Yeji Shin , Maria G. Balaguer , Paola Campo , Selen Dirik , Bryan A. Montoya , Gregory M.R. Cook , Gabrielle M. Palermo , Parsa K. Naghshineh , Alex Morgan , Sara R.M.U. Rahman , Abraham A. Palmer , Francesca Telese , Giordano de Guglielmo

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引用次数: 0

Abstract

The use of fentanyl and other opioids during pregnancy is a pressing public health issue due to its association with Neonatal Opioid Withdrawal Syndrome (NOWS) and long-term neurobehavioral deficits. Human epidemiologic studies are confounded by both genetic and environmental factors that differ between exposed and unexposed children. We developed a novel rat model of perinatal fentanyl exposure in heterogeneous stock (HS) rats characterized by high genetic diversity, to investigate NOWS symptoms and its long-term effects on adult fentanyl self-administration, drug-seeking behavior, and central amygdala (CeA) transcriptomic changes, addressing a critical gap in understanding synthetic opioid impacts. Offspring born to fentanyl-exposed dams exhibited reduced survival, lower body weight, spontaneous withdrawal symptoms, and mechanical hypersensitivity during adolescence. These rats displayed negative affect in adolescence, while they showed increased fentanyl self-administration, heightened drug-seeking during reinstatement, and elevated corticosterone levels during withdrawal in adulthood. To explore the molecular underpinnings of these physiological and behavioral outcomes, we conducted RNA-seq in the CeA of adult rats, revealing dysregulated pathways related to GPCR signaling, adaptive immune response and neurodevelopmental processes. These transcriptional changes provide insights into the mechanisms driving addiction vulnerability and stress-related behaviors following early fentanyl exposure. Our findings highlight the lasting impact of perinatal opioid exposure in an experimental system that avoids many of the confounds that plague studies in humans, underscoring the need for preclinical models to study NOWS and its long-term consequences. This model offers translational relevance for developing therapeutic strategies to mitigate NOWS and reduce neuropsychiatric risks associated with perinatal opioid exposure.

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围产期芬太尼暴露导致持久的成瘾风险和中央杏仁核基因失调

怀孕期间芬太尼和其他阿片类药物的使用是一个紧迫的公共卫生问题，因为它与新生儿阿片类药物戒断综合征（NOWS）和长期神经行为缺陷有关。人类流行病学研究受到遗传和环境因素的干扰，这些因素在暴露儿童和未暴露儿童之间存在差异。我们建立了一种具有高遗传多样性的异种种群（HS）大鼠围产期芬太尼暴露的新大鼠模型，以研究NOWS症状及其对成年芬太尼自我给药、药物寻找行为和中央杏仁核（CeA）转录组变化的长期影响，解决了理解合成阿片类药物影响的关键空白。芬太尼暴露的母鼠所生的后代在青春期表现出存活率降低、体重下降、自发戒断症状和机械过敏。这些大鼠在青春期表现出负面影响，而它们在恢复期间表现出芬太尼自我给药增加，药物寻求增加，并且在成年期戒断期间皮质酮水平升高。为了探索这些生理和行为结果的分子基础，我们对成年大鼠的CeA进行了rna测序，揭示了与GPCR信号、适应性免疫反应和神经发育过程相关的失调通路。这些转录变化为早期芬太尼暴露后驱动成瘾脆弱性和压力相关行为的机制提供了见解。我们的研究结果强调了围产期阿片类药物暴露在实验系统中的持久影响，该实验系统避免了许多困扰人类研究的混淆，强调了临床前模型研究NOWS及其长期后果的必要性。该模型为开发治疗策略以减轻NOWS和减少与围产期阿片类药物暴露相关的神经精神风险提供了翻译相关性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).