The Effects of Perinatal Oxycodone Exposure on Behavioral Outcome in a Rodent Model

Sithisarn, Thitinart; Legan, Sandra J.; Westgate, Philip M.; Wilson, Melinda E.; Wellmann, Kristen A.; Bada, Henrietta S.; Barron, Susan

doi:10.3389/fped.2017.00180

Cited by 26 publications

(36 citation statements)

References 88 publications

(97 reference statements)

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“…Orally-administered analgesics are the most common form of pain relief prescribed after caesarian sections 12,13 , and oral oxy administration has been shown to be safer than and as effective as intravenous administration of other opioids 9,14,15 . Previous oxy studies have shown deficits such as behavioral impairments and disruption in both OPRM1 and endothelin receptor expression during development in offspring exposed to oxy in utero [16][17][18][19] . However, these studies focused primarily on prenatal oxy exposure, leaving a large gap in the knowledge regarding postnatal oxy exposure.…”

Section: Introductionmentioning

confidence: 95%

Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure

et al. 2020

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Prescription opioid abuse during and after pregnancy is a rising public health concern. While earlier studies have documented that offspring exposed to opioids in utero have impaired neurodevelopment, a significant knowledge gap remains in comparing the overall development between offspring exposed in utero and postnatally. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. To fill in these important knowledge gaps, the current study uses a preclinical rat model mimicking oxycodone (oxy) exposure in utero (IUO) and postnatally (PNO) to investigate comparative and intergenerational effects in the two different treatment groups. While significant phenotypic attributes were observed with the two treatments and across the two generations, RNA sequencing revealed alterations in the expression of key synaptic genes in the two exposed groups in both generations. RNA sequencing and post validation of genes using RT-PCR highlighted the differential expression of several neuropeptides associated with the hypocretin system, a system recently implicated in addiction. Further, behavior studies revealed anxiety-like behaviors and social deficits that persisted even in the subsequent generations in the two treatment groups. To summarize, our study for the first time reveals a new line of investigation on the potential risks associated with oxy use during and after pregnancy, specifically the disruption of neurodevelopment and intergenerational impact on behavior.

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Section: Introductionmentioning

confidence: 95%

Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure

et al. 2020

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“…However, a human study by Seaton et al has shown that oxy is concentrated in the breastmilk and offspring exposed via the breastmilk may receive less than 10% of a typical therapeutic oral infant dose (0.1-0.2 mg/kg) [32][33][34][35][36]. Despite this low dose, infant exposure to oxy via the breastmilk has been associated with central nervous system depression [37], and a number of animal studies have also revealed deficits in behavior and development associated with perinatal opioid exposure [12,[38][39][40]. Additionally, opiates can pass into the placenta and act on fetal opioid receptors [23][24][25].…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Extracellular Vesicle microRNA Signatures Associated with In Utero and Postnatal Oxycodone Exposure

Shahjin

Guda

Schaal

et al. 2019

Cells

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Oxycodone (oxy) is a semi-synthetic opioid commonly used as a pain medication that is also a widely abused prescription drug. While very limited studies have examined the effect of in utero oxy (IUO) exposure on neurodevelopment, a significant gap in knowledge is the effect of IUO compared with postnatal oxy (PNO) exposure on synaptogenesis-a key process in the formation of synapses during brain development-in the exposed offspring. One relatively unexplored form of cell-cell communication associated with brain development in response to IUO and PNO exposure are extracellular vesicles (EVs). EVs are membrane-bound vesicles that serve as carriers of cargo, such as microRNAs (miRNAs). Using RNA-Seq analysis, we identified distinct brain-derived extracellular vesicle (BDEs) miRNA signatures associated with IUO and PNO exposure, including their gene targets, regulating key functional pathways associated with brain development to be more impacted in the IUO offspring. Further treatment of primary 14-day in vitro (DIV) neurons with IUO BDEs caused a significant reduction in spine density compared to treatment with BDEs from PNO and saline groups. In summary, our studies identified for the first time, key BDE miRNA signatures in IUO-and PNO-exposed offspring, which could impact their brain development as well as synaptic function.Cells 2020, 9, 21 2 of 18 lack of studies that have compared the effect of in utero oxy (IUO) and postnatal oxy (PNO) exposure on synaptogenesis-a key process of the formation of synapses during brain development-in the exposed offspring. Synapses are key communication points between neurons, which play a critical role in the regulation of neurotransmission and brain plasticity [6].One relatively unexplored form of cell-cell communication associated with brain development in response to IUO and PNO exposure is extracellular vesicles (EVs) [7][8][9]. These membrane-bound vesicles, comprised of exosomes and microvesicles, originate from the multivesicular bodies and plasma membrane, respectively. Furthermore, these EVs, which carry a repertoire of cargo, including microRNAs (miRNAs), are shown to induce inflammation and subsequent neuronal damage, thus serving as key mediators of pathogenesis in several neurological and neurodegenerative disorders [10,11]. The main objective of this study was to identify differentially expressed BDEs miRNAs using RNA sequencing (RNA-Seq) and evaluate their impact on synaptic architecture during a key stage of brain development.

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“…Prenatal opioid exposure has also been shown to induce hyperactivity upon novelty in adolescent and adult offspring (Lasky et al, 1977;Zhu and Stadlin, 2000;Timár et al, 2010;Sithisarn et al, 2017). Interestingly, a link between an animal's hyperactivity in a novel environment and a higher propensity for developing drug sensitization or drug selfadministration has been proposed for several classes of drugs, including opioids (Piazza et al, 1989;Piazza and Le Moal, 1996;Suto et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

A Monoclonal Antibody against 6-Acetylmorphine Protects Female Mice Offspring from Adverse Behavioral Effects Induced by Prenatal Heroin Exposure

Kvello

Andersen

Øiestad

et al. 2018

J Pharmacol Exp Ther

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Escalating opioid use among fertile women has increased the number of children being exposed to opioids during fetal life. Furthermore, accumulating evidence links prenatal opioid exposure, including opioid maintenance treatment, to longterm negative effects on cognition and behavior, and presses the need to explore novel treatment strategies for pregnant opioid users. The present study examined the potential of a monoclonal antibody (mAb) targeting heroin's first metabolite, 6-acetylmorphine (6-AM), in providing fetal protection against harmful effects of prenatal heroin exposure in mice. First, we examined anti-6-AM mAb's ability to block materno-fetal transfer of active metabolites after maternal heroin administration. Next, we studied whether maternal mAb pretreatment could prevent adverse effects in neonatal and adolescent offspring exposed to intrauterine heroin (3 Â 1.05 mg/kg). Anti-6-AM mAb pretreatment of pregnant dams profoundly reduced the distribution of active heroin metabolites to the fetal brain. Furthermore, maternal mAb administration prevented hyperactivity and drug sensitization in adolescent female offspring prenatally exposed to heroin. Our findings demonstrate that passive immunization with a 6-AM-specific antibody during pregnancy provides fetal neuroprotection against heroin metabolites, and thereby prevents persistent adverse behavioral effects in the offspring. An immunotherapeutic approach to protect the fetus against long-term effects of prenatal drug exposure has not been reported previously, and should be further explored as prophylactic treatment of pregnant heroin users susceptible to relapse.

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The Effects of Perinatal Oxycodone Exposure on Behavioral Outcome in a Rodent Model

Cited by 26 publications

References 88 publications

Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure

Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure

Brain-Derived Extracellular Vesicle microRNA Signatures Associated with In Utero and Postnatal Oxycodone Exposure

A Monoclonal Antibody against 6-Acetylmorphine Protects Female Mice Offspring from Adverse Behavioral Effects Induced by Prenatal Heroin Exposure

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