Dataset Information

Pharmacological Prevention of Neonatal Opioid Withdrawal in a Pregnant Guinea Pig Model.

ABSTRACT: Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective opioid antagonist, 6β-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS, and a therapeutic mechanism was proposed based on preferential delivery of 6BN to fetal brain with relative exclusion from maternal brain. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 ∼0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies in rodents and non-human primates. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This high potency appears to run counter to our pharmacokinetic studies showing slow 6BN transit of both the placenta and maternal blood brain barrier in guinea pigs, and calls into question the preferential delivery mechanism. Rather, it suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence at all developmental stages, even in adults, as compared to its well-established low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.

SUBMITTER: Safa A

PROVIDER: S-EPMC7953910 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundCytomegalovirus (CMV) is a leading infectious cause of neurologic deficits, both in the settings of congenital and perinatal infection, but few animal models exist to study neurodevelopmental outcomes. This study examined the impact of neonatal guinea pig CMV (GPCMV) infection on spatial learning and memory in a Morris water maze (MWM) model.MethodsNewborn pups were challenged intraperitoneally (i.p.) with a pathogenic red fluorescent protein-tagged GPCMV, or sham inoculated. On days 15-19 post infection (p.i.), pups were tested in the MWM. Viral loads were measured in blood and tissue by quantitative PCR (qPCR), and brain samples collected at necropsy were examined by histology and immunohistochemistry.ResultsViremia (DNAemia) was detected at day 3 p.i. in 7/8 challenged animals. End-organ dissemination was observed, by qPCR, in the lung, liver, and spleen. CD4-positive (CD4+) and CD8-positive (CD8+) T cell infiltrates were present in brains of challenged animals, particularly in periventricular and hippocampal regions. Reactive gliosis and microglial nodules were observed. Statistically significant spatial learning and memory deficits were observed by MWM, particularly for total maze distance traveled (p < 0.0001).ConclusionNeonatal GPCMV infection in guinea pigs results in cognitive defects demonstrable by the MWM. This neonatal guinea pig challenge model can be exploited for studying antiviral interventions.ImpactCMV impairs neonatal neurocognition and memory in the setting of postnatal infection. The MWM can be used to examine memory and learning in a guinea pig model of neonatal CMV infection. CD4+ and CD8+ T cells infiltrate the brain following neonatal CMV challenge. This article demonstrates that the MWM can be used to evaluate memory and learning after neonatal GPCMV challenge. The guinea pig can be used to examine central nervous system pathology caused by neonatal CMV infection and this attribute may facilitate the study of vaccines and antivirals.

Project description:The opioid epidemic in the United States has led to a significant increase in the incidence of neonatal opioid withdrawal syndrome (NOWS); however, the understanding of long-term consequences of NOWS is limited. The objective of this study was to evaluate post-discharge healthcare utilization in infants with NOWS and examine the association between NOWS severity and healthcare utilization. A retrospective cohort design was used to ascertain healthcare utilization in the first year after birth-related discharge using the CERNER Health Facts® database. ICD-9/ICD-10 diagnostic codes were used to identify live births and to classify infants into two study groups: NOWS and uncomplicated births (a 25% random sample). Evaluated outcomes included rehospitalization, emergency department (ED) visits within 30-days and one-year after discharge, and a composite one-year utilization event (either hospitalization or emergency department visit during that year). NOWS severity was operationalized as pharmacologic treatment, length of hospitalization, and medical conditions often associated with NOWS. In 3,526 infants with NOWS (restricted to gestational age ≥ 33 weeks), NOWS severity was associated with an increase in composite one-year utilization (OR: 1.1; 95% CI: 1.04-1.2) after adjusting for prematurity, sepsis, jaundice, use of antibiotics, infant sex, insurance status, race, hospital bed size, year of birth, and census division. In a subset of full-term infants (3008 with NOWS and 88,452 uncomplicated births), having a NOWS diagnosis was associated with higher odds of a 30-day (OR: 1.6; 95% CI: 1.03-2.4) and one-year rehospitalization (OR: 1.6; 95% CI: 1.1-2.4) after adjusting for infant sex, race, type of medical insurance, hospital location, census division, year of primary encounter, hospital bed size, and medical conditions. This study found higher healthcare utilization during the first year of life in infants diagnosed with NOWS, especially those with severe NOWS. Findings suggest a need for closer post-discharge follow-up and management of infants with NOWS.

Project description:ImportancePrescription opioids are often used during pregnancy even though they are associated with neonatal opioid withdrawal syndrome (NOWS). Most studies of adverse outcomes of opioid use for pain have assessed only the class-wide outcome despite the pharmacodynamic and pharmacokinetic heterogeneity across opioid medications.ObjectiveTo compare the risk of NOWS across common types of opioids when prescribed as monotherapy during the last 3 months of pregnancy.Design, setting, and participantsThis cohort study analyzed administrative claims data of Medicaid-insured mothers and newborns in 46 states and Washington DC from January 1, 2000, through December 31, 2014. Participants were mothers with 2 or more dispensed opioid prescriptions within 90 days before delivery and their eligible live-born neonates. Data were analyzed from February 2020 to March 2021.ExposureDifferent types of opioid medications were compared by agonist strength (strong vs weak) and half-life (medium vs short and long vs short) of the opioid active ingredient.Main outcomes and measuresThe primary outcome was NOWS, which was identified using an International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code in the 30 days after delivery. Relative risks (RRs) were adjusted for an exposure propensity score, including demographic characteristics, comorbidities, other medication use, and opioid treatment characteristics (including morphine milligram equivalents), using fine stratification.ResultsThe cohort comprised 48 202 opioid-exposed pregnancies with live newborns. A total of 1069 neonates (2.2%) had NOWS and 559 (1.2%) had severe NOWS. Opioid exposure during pregnancy included 16 202 pregnancies exposed to codeine, 4540 to oxycodone, 1244 to tramadol, 260 to methadone (dispensed for pain), 90 to hydromorphone, and 63 to morphine compared with 25 710 exposed to hydrocodone. Demographic characteristics varied across opioids, with tramadol, oxycodone, methadone, hydromorphone, and morphine being more commonly dispensed at older maternal age (≥35 years). Compared with hydrocodone, codeine had a lower adjusted RR of NOWS (0.57; 95% CI, 0.46-0.70), with a similar adjusted RR for tramadol (RR, 1.06; 95% CI, 0.73-1.56), and 2- to 3-fold higher adjusted RRs for oxycodone (1.87; 95% CI, 1.66-2.11), morphine (2.84; 95% CI, 1.30-6.22), methadone (3.02; 95% CI, 2.45-3.73), and hydromorphone (2.03; 95% CI, 1.09-3.78). Strong agonists were associated with a higher risk of NOWS than weak agonists (RR, 1.97; 95% CI, 1.78-2.17), and long half-life opioids were associated with an increased risk compared with short half-life products (RR, 1.33; 95% CI, 1.12-1.56). Findings were consistent across sensitivity and subgroup analyses.Conclusions and relevanceResults of this study show higher risk of NOWS and severe NOWS among neonates with in utero exposure to strong agonists and long half-life prescription opioids. Information on the opioid-specific risk of NOWS may help prescribers select opioids for pain management in late stages of pregnancy.

Dataset Information

Pharmacological Prevention of Neonatal Opioid Withdrawal in a Pregnant Guinea Pig Model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets