Sex differences in neonatal outcomes following prenatal opioid exposure

Madurai, Nethra K.; Jantzie, Lauren L.; Yen, Elizabeth

doi:10.3389/fped.2024.1357970

Cited by 4 publications

References 91 publications

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

Wingfield,

Misic,

Jain

et al. 2024

Psychopharmacology

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

Wingfield,

Misic,

Jain

et al. 2024

Psychopharmacology

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Methadone directly impairs central nervous system cells in vitro

De Gregorio,

Gallardo,

Berríos-Cárcamo

et al. 2024

Sci Rep

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Methadone is a synthetic long-acting opioid that is increasingly used in the replacement therapy of opioid-addicted patients, including pregnant women. However, methadone therapy in this population poses challenges, as it induces cognitive and behavioral impairments in infants exposed to this opioid during prenatal development. In animal models, prenatal methadone exposure results in detrimental consequences to the central nervous system, such as: (i) increased neuronal apoptosis; (ii) disruption of oligodendrocyte maturation and increased apoptosis and (iii) increased microglia and astrocyte activation. However, it remains unclear whether these deleterious effects result from a direct effect of methadone on brain cells. Therefore, our goal was to uncover the impact of methadone on single brain cell types in vitro. Primary cultures of rat neurons, oligodendrocytes, microglia, and astrocytes were treated for three days with 10 µM methadone to emulate a chronic administration. Apoptotic neurons were identified by cleaved caspase-3 detection, and synaptic density was assessed by the juxtaposition of presynaptic and postsynaptic markers. Apoptosis of oligodendrocyte precursors was determined by cleaved caspase-3 detection. Oligodendrocyte myelination was assessed by immunofluorescence, while microglia and astrocyte proinflammatory activation were assessed by both immunofluorescence and RT-qPCR. Methadone treatment increased neuronal apoptosis and reduced synaptic density. Furthermore, it led to increased oligodendrocyte apoptosis and a reduction in the myelinating capacity of these cells, and promoted the proinflammatory activation of microglia and astrocytes. We showed that methadone, the most widely used drug in opioid replacement therapy for pregnant women with opioid addiction, directly impairs brain cells in vitro, highlighting the need for developing alternative therapies to address opioid addiction in this population.

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Spectrotemporal profiling of ultrasonic vocalizations during neonatal opioid withdrawal reveals a kappa opioid receptor component in female mice

Wingfield,

Misic,

Jain

et al. 2024

Preprint

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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. Current treatments involve non-pharmacological and pharmacological interventions, however, there is no one standardized approach, in part because of variability in NOWS severity. To effectively model NOWS traits in mice, we used a third trimester-approximate opioid exposure paradigm, where neonatal inbred FVB/NJ and outbred Carworth Farms White(CFW) pups were injected twice-daily with morphine(10-15mg/kg, s.c.) or saline(0.9%, 20 ul/g, s.c.) from postnatal day(P) one to P14. We observed reduced body weight gain, hypothermia, thermal hyperalgesia, and increased ultrasonic vocalizations(USVs). Neonatal USVs are emitted exclusively in isolation to communicate distress and thus serve as a model behavior for affective states. On P14, we observed altered USV syllable profiles during spontaneous morphine withdrawal, including an increase in Complex 3 syllables in FVB/NJ females(but not males) and in CFW mice of both sexes. Brainstem transcriptomics revealed an upregulation of the kappa opioid receptor(Oprk1), whose activation has previously been shown to contribute to withdrawal-induced dysphoria. Treatment with the kappa opioid receptor(KOR) antagonist, nor-BNI(30 mg/kg, s.c.), significantly reduced USV emission in FVB/NJ females, but not FVB/NJ males during spontaneous morphine withdrawal. Furthermore, treatment with the KOR agonist, U50,488h(0.625 mg/kg, s.c.), was sufficient to increase USV emission on P10(both sexes) and on P14(females only) in FVB/NJ mice. Together, these results indicate a female-specific recruitment of the dynorphin/KOR system in neonatal opioid withdrawal symptom severity.

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Sex differences in neonatal outcomes following prenatal opioid exposure

Cited by 4 publications

References 91 publications

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

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

Methadone directly impairs central nervous system cells in vitro

Spectrotemporal profiling of ultrasonic vocalizations during neonatal opioid withdrawal reveals a kappa opioid receptor component in female mice

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