PDF(Pubmed)
Abstract：
Prenatal opioid exposure is a major health concern in the United States, with the incidence of neonatal opioid withdrawal syndrome (NOWS) escalating in recent years. NOWS occurs upon cessation of in utero opioid exposure and is characterized by increased irritability, disrupted sleep patterns, high-pitched crying, and dysregulated feeding. The main pharmacological strategy for alleviating symptoms is treatment with replacement opioids. The neural mechanisms mediating NOWS and the long-term neurobehavioral effects are poorly understood. We used a third trimester-approximate model in which neonatal outbred pups (Carworth Farms White; CFW) were administered once-daily morphine (15 mg/kg, s.c.) from postnatal day (P) day 1 through P14 and were then assessed for behavioral and transcriptomic adaptations within the nucleus accumbens (NAc) on P15. We also investigated the long-term effects of perinatal morphine exposure on adult learning and reward sensitivity. We observed significant weight deficits, spontaneous thermal hyperalgesia, and altered ultrasonic vocalization (USV) profiles following repeated morphine and during spontaneous withdrawal. Transcriptome analysis of NAc from opioid-withdrawn P15 neonates via bulk mRNA sequencing identified an enrichment profile consistent with downregulation of myelin-associated transcripts. Despite the neonatal behavioral and molecular effects, there were no significant long-term effects of perinatal morphine exposure on adult spatial memory function in the Barnes Maze, emotional learning in fear conditioning, or in baseline or methamphetamine-potentiated reward sensitivity as measured via intracranial self-stimulation. Thus, the once daily third trimester-approximate exposure regimen, while inducing NOWS model traits and significant transcriptomic effects in neonates, had no significant long-term effects on adult behaviors.
摘要：
在美国，产前阿片类药物暴露是一个主要的健康问题，随着近年来新生儿阿片类药物戒断综合征（NOWS）的发病率不断上升。NOWS发生在子宫内阿片类药物接触停止后，其特征是易怒性增加，被打乱的睡眠模式,高声哭泣，和饮食失调。缓解症状的主要药理学策略是用替代阿片类药物治疗。对介导NOWS和长期神经行为效应的神经机制知之甚少。我们使用了第三个三个月的近似模型，其中新生儿近交幼崽（CarworthFarmsWhite；CFW）每天服用一次吗啡（15mg/kg，s.c.）从出生后第1天（P）天到P14，然后在P15上评估伏隔核（NAc）内的行为和转录组适应。我们还研究了围产期吗啡暴露对成人学习和奖励敏感性的长期影响。我们观察到明显的体重不足，自发性热痛觉过敏,反复使用吗啡和自发戒断期间，超声发声（USV）改变。通过批量mRNA测序对阿片类药物撤回的P15新生儿的NAc进行转录组分析，发现了与髓磷脂相关转录本下调一致的富集谱。尽管新生儿的行为和分子效应，在巴恩斯迷宫中，围产期吗啡暴露对成人空间记忆功能没有显著的长期影响，恐惧条件下的情感学习，或通过颅内自我刺激测量的基线或甲基苯丙胺增强的奖赏敏感性。因此，每日一次的妊娠晚期-近似暴露方案，在诱导新生儿NOWS模型性状和显著的转录组效应的同时，对成人行为没有显著的长期影响。
