Wingfield Kelly K, Misic Teodora, Jain Kaahini, McDermott Carly S, Abney Nalia M, Richardson Kayla T, Rubman Mia B, Beierle Jacob A, Miracle Sophia A, Sandago Emma J, Baskin Britahny M, Lynch William B, Borrelli Kristyn N, Yao Emily J, Wachman Elisha M, Bryant Camron D
Laboratory of Addiction Genetics, Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA USA.
T32 Biomolecular Pharmacology Training Program, Boston University Chobanian & Avedisian School of Medicine, Boston, MA USA.
bioRxiv. 2024 Sep 1:2024.07.02.601766. doi: 10.1101/2024.07.02.601766.
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.
We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal.
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.
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 (, 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.
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.
孕期使用阿片类药物会导致不良的婴儿健康后果，包括新生儿阿片类药物戒断综合征（NOWS）。NOWS包括在自然戒断期间出现的胃肠道、自主神经系统和神经功能障碍。NOWS严重程度的差异需要更个体化的治疗方法。新生小鼠的超声发声（USV）作为一种应激反应单独发出，并且在阿片类药物戒断期间增加，从而模拟一种可用于测试新治疗方法的负面情绪状态。
我们试图确定新生儿阿片类药物戒断期间的行为和USV特征、脑干转录组适应性以及κ阿片受体在USV中的作用。
我们采用了一种接近孕晚期的阿片类药物暴露模型，从出生后第1天（P1）到P14，每天给新生的近交系FVB/NJ幼崽皮下注射两次吗啡（10mg/kg）或生理盐水（0.9%，20μl/g）。该方案会导致体重增加减少、体温过低、热痛觉过敏，以及在吗啡自然戒断期间USV增加。
在P14时，戒断期间USV发出增加且USV音节改变，包括FVB/NJ雌性（而非雄性）中复杂3音节增加。脑干大量mRNA测序显示κ阿片受体上调，这导致戒断引起的烦躁不安。κ阿片受体（KOR）拮抗剂nor-BNI（30mg/kg，皮下注射）在吗啡自然戒断期间显著减少了FVB/NJ雌性的USV，但对雄性无效。此外，KOR激动剂U50,488h（0.625mg/kg，皮下注射）足以在FVB/NJ小鼠的P10（雌雄均有）和P14（仅雌性）时增加USV。
我们确定了一种升高的USV音节，即复杂3，以及强啡肽/KOR系统在与新生儿阿片类药物戒断严重程度相关的USV增加中的雌性特异性募集。
