The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice.

IF 3.5 3区医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-09-30 DOI:10.1007/s00213-024-06694-7

Kelly K Wingfield, Teodora Misic, Kaahini Jain, Carly S McDermott, Nalia M Abney, Kayla T Richardson, Mia B Rubman, Jacob A Beierle, Sophia A Miracle, Emma J Sandago, Britahny M Baskin, William B Lynch, Kristyn N Borrelli, Emily J Yao, Elisha M Wachman, Camron D Bryant

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引用次数: 0

Abstract

Rationale: Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments.

Objectives: We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal.

Methods: We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal.

Results: On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice.

Conclusions: We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

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新生儿阿片戒断期间的超声波发声（USV）音节剖面以及雌性小鼠的卡巴阿片受体对增加USV发声的作用。

依据：孕期使用阿片类药物会对婴儿健康造成不良影响，包括新生儿阿片类药物戒断综合征（NOWS）。新生儿阿片类药物戒断综合征包括胃肠道、自主神经系统和神经系统功能障碍，表现为自发性戒断。由于 NOWS 的严重程度各不相同，因此有必要采取更加个性化的治疗方法。新生小鼠的超声波发声（USVs）是一种应激反应，在阿片类药物戒断期间会增加，从而模拟出一种负面情绪状态，可用于测试新的治疗方法：我们试图确定新生儿阿片戒断期间的行为和USV特征、脑干转录组适应性以及卡巴阿片受体在USV中的作用：我们采用了一种近似阿片类药物暴露模型，即从出生后第1天到第14天，每天两次给近交系FVB/NJ幼崽注射吗啡（10毫克/千克，静脉注射）或生理盐水（0.9%，20毫升/克，静脉注射）。该方案可在自发吗啡戒断期间诱导体重增加减少、低体温、热痛和USV增加：结果：在P14，戒断期间USV发射增加，USV音节改变，包括FVB/NJ雌性（而非雄性）的Complex 3音节增加。脑干大量mRNA测序显示，卡巴阿片受体（Oprk1）上调，而卡巴阿片受体是戒断诱发镇静障碍的原因之一。卡巴阿片受体（KOR）拮抗剂nor-BNI（30 mg/kg，s.c.）能显著降低FVB/NJ雌性动物在自发吗啡戒断过程中的USV，但不能降低雄性动物的USV。此外，KOR激动剂U50,488h（0.625 mg/kg，s.c.）足以增加FVB/NJ小鼠P10（雌雄）和P14（仅雌性）的USV：结论：我们在与新生儿阿片戒断严重程度相关的 USVs 增加中发现了一个升高的 USV 音节--复合 3，以及雌性特有的达吗啡/KOR 系统招募。

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

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.