Brain structural connectome in neonates with prenatal opioid exposure

Vishnubhotla, Ramana V.; Zhao, Yi; Dietrich, Jonathan; Sokol, Gregory M.; Sadhasivam, Senthilkumar; Radhakrishnan, Rupa

doi:10.3389/fnins.2022.952322

Cited by 7 publications

(3 citation statements)

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“…Regional, bulk cell-type, and single cell sequencing are likely to highlight more specific pathways in the future, for example, in the dopamine and microglial systems. We conclude that in utero or early post-natal exposure to specific opioids has the capacity to impact neuronal circuity ( Salzwedel et al, 2020 ; Radhakrishnan et al, 2022 ; Vishnubhotla et al, 2022 ) with long-lasting effects in select behaviors that outlast the alterations to gene activation. The comparisons of perinatal and adult datasets highlight the large number of diverse genes that contribute to various pathways, so that phenotypic responses may overlap considerably more than transcriptional responses.…”

Section: Discussionmentioning

confidence: 90%

Molecular and long-term behavioral consequences of neonatal opioid exposure and withdrawal in mice

Dunn

Robinson

Nwokafor

et al. 2023

Front. Behav. Neurosci.

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IntroductionInfants exposed to opioids in utero are at high risk of exhibiting Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of somatic withdrawal symptoms including high pitched crying, sleeplessness, irritability, gastrointestinal distress, and in the worst cases, seizures. The heterogeneity of in utero opioid exposure, particularly exposure to polypharmacy, makes it difficult to investigate the underlying molecular mechanisms that could inform early diagnosis and treatment of NOWS, and challenging to investigate consequences later in life.MethodsTo address these issues, we developed a mouse model of NOWS that includes gestational and post-natal morphine exposure that encompasses the developmental equivalent of all three human trimesters and assessed both behavior and transcriptome alterations.ResultsOpioid exposure throughout all three human equivalent trimesters delayed developmental milestones and produced acute withdrawal phenotypes in mice reminiscent of those observed in infants. We also uncovered different patterns of gene expression depending on the duration and timing of opioid exposure (3-trimesters, in utero only, or the last trimester equivalent only). Opioid exposure and subsequent withdrawal affected social behavior and sleep in adulthood in a sex-dependent manner but did not affect adult behaviors related to anxiety, depression, or opioid response.DiscussionDespite marked withdrawal and delays in development, long-term deficits in behaviors typically associated with substance use disorders were modest. Remarkably, transcriptomic analysis revealed an enrichment for genes with altered expression in published datasets for Autism Spectrum Disorders, which correlate well with the deficits in social affiliation seen in our model. The number of differentially expressed genes between the NOWS and saline groups varied markedly based on exposure protocol and sex, but common pathways included synapse development, the GABAergic and myelin systems, and mitochondrial function.

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Section: Discussionmentioning

confidence: 90%

Molecular and long-term behavioral consequences of neonatal opioid exposure and withdrawal in mice

Dunn

Robinson

Nwokafor

et al. 2023

Front. Behav. Neurosci.

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“…A significant challenge is distinguishing the neurobiological effects of opioid agonists from various other confounding factors, including tobacco, alcohol, nonmedical drugs, environmental influences, and additional medical risks ( Logan et al, 2013 ; Radhakrishnan et al, 2022a ; Radhakrishnan et al, 2022b ). The effects of opioids during pregnancy extend beyond nociceptive processes to include effects on gastrointestinal, endocrine, and autonomic functions as well as cognition, behavior, and reward circuitry for the mother and developing fetus, and subsequently the offspring ( Radhakrishnan et al, 2021 ; Radhakrishnan et al, 2022a ; Radhakrishnan et al, 2022b ; Radhakrishnan et al, 2022c ; Vishnubhotla et al, 2022 ; Wise et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Placental cytochrome P450 methylomes in infants exposed to prenatal opioids: exploring the effects of neonatal opioid withdrawal syndrome on health horizons

Radhakrishna,

Sadhasivam,

Radhakrishnan

et al. 2024

Front. Genet.

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Background: Neonatal opioid withdrawal syndrome (NOWS), arises due to increased opioid use during pregnancy. Cytochrome P450 (CYP) enzymes play a pivotal role in metabolizing a wide range of substances in the human body, including opioids, other drugs, toxins, and endogenous compounds. The association between CYP gene methylation and opioid effects is unexplored and it could offer promising insights.Objective: To investigate the impact of prenatal opioid exposure on disrupted CYPs in infants and their anticipated long-term clinical implications.Study Design: DNA methylation levels of CYP genes were analyzed in a cohort of 96 placental tissues using Illumina Infinium MethylationEPIC (850 k) BeadChips. This involved three groups of placental tissues: 32 from mothers with infants exposed to opioids prenatally requiring pharmacologic treatment for NOWS, 32 from mothers with prenatally opioid-exposed infants not needing NOWS treatment, and 32 from unexposed control mothers.Results: The study identified 20 significantly differentially methylated CpG sites associated with 17 distinct CYP genes, with 14 CpGs showing reduced methylation across 14 genes (CYP19A1, CYP1A2, CYP4V2, CYP1B1, CYP24A1, CYP26B1, CYP26C1, CYP2C18, CYP2C9, CYP2U1, CYP39A1, CYP2R1, CYP4Z1, CYP2D7P1 and), while 8 exhibited hypermethylation (CYP51A1, CYP26B1, CYP2R1, CYP2U1, CYP4X1, CYP1A2, CYP2W1, and CYP4V2). Genes such as CYP1A2, CYP26B1, CYP2R1, CYP2U1, and CYP4V2 exhibited both increased and decreased methylation. These genes are crucial for metabolizing eicosanoids, fatty acids, drugs, and diverse substances.Conclusion: The study identified profound methylation changes in multiple CYP genes in the placental tissues relevant to NOWS. This suggests that disruption of DNA methylation patterns in CYP transcripts might play a role in NOWS and may serve as valuable biomarkers, suggesting a future pathway for personalized treatment. Further research is needed to confirm these findings and explore their potential for diagnosis and treatment.

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“…Clinical studies have demonstrated that perinatal exposure to opioids can lead to long-lasting consequences such as cognitive deficits and sensorimotor impairments ( Mactier and Hamilton, 2020 ). Recent imaging studies have also reported low-term changes in neural functioning after opioid exposure ( Radhakrishnan et al, 2022 ; Vishnubhotla et al, 2022 ). These studies, however, were primarily focused on heroin and methadone and may not represent the effects of high-potency synthetic opioids like fentanyl.…”

Section: Introductionmentioning

confidence: 99%

Effects of neonatal fentanyl on late adolescent opioid-mediated behavior

Crawford

Taylor²,

Park³

et al. 2023

Front. Neurosci.

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IntroductionBecause of the steady increase in the use of synthetic opioids in women of childbearing age, a large number of children are at risk of exposure to these drugs prenatally or postnatally through breast milk. While there is older literature looking at the effects of morphine and heroin, there are relatively few studies looking at the long-term effects of high-potency synthetic opioid compounds like fentanyl. Thus, in the present study, we assessed whether brief exposure to fentanyl in male and female rat pups during a period roughly equivalent to the third trimester of CNS development altered adolescent oral fentanyl self-administration and opioid-mediated thermal antinociception.MethodsWe treated the rats with fentanyl (0, 10, or 100 μg/kg sc) from postnatal day (PD) 4 to PD 9. The fentanyl was administered daily in two injections given 6 h apart. After the last injection on PD 9, the rat pups were left alone until either PD 40 where they began fentanyl self-administration training or PD 60 where they were tested for morphine- (0, 1.25, 2.5, 5, or 10 mg/kg) or U50,488- (0, 2.5, 5, 10, or 20 mg/kg) induced thermal antinociception.ResultsIn the self-administration study, we found that female rats had more active nose pokes than male rats when receiving a fentanyl reward but not sucrose alone solution. Early neonatal fentanyl exposure did not significantly alter fentanyl intake or nose-poke response. In contrast, early fentanyl exposure did alter thermal antinociception in both male and female rats. Specifically, fentanyl (10 μg/kg) pre-treatment increased baseline paw-lick latencies, and the higher dose of fentanyl (100 μg/kg) reduced morphine-induced paw-lick latencies. Fentanyl pre-treatment did not alter U50,488-mediated thermal antinociception.ConclusionsAlthough our exposure model is not reflective of typical human fentanyl use during pregnancy, our study does illustrate that even brief exposure to fentanyl during early development can have long-lasting effects on mu-opioid-mediated behavior. Moreover, our data suggest that females may be more susceptible to fentanyl abuse than males.

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Brain structural connectome in neonates with prenatal opioid exposure

Cited by 7 publications

References 85 publications

Molecular and long-term behavioral consequences of neonatal opioid exposure and withdrawal in mice

Molecular and long-term behavioral consequences of neonatal opioid exposure and withdrawal in mice

Placental cytochrome P450 methylomes in infants exposed to prenatal opioids: exploring the effects of neonatal opioid withdrawal syndrome on health horizons

Effects of neonatal fentanyl on late adolescent opioid-mediated behavior

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