Evidence map›Paper›PMID 39182528›Full record

ArticleNeurotoxicology and teratology

Differences in withdrawal symptoms, microglia activity, and cognitive functioning in rats exposed to continuous low-dose heroin in-utero.

Sara L Mills-Huffnagle, Charles N Zawatsky, Gjhvona Bryant, Michael Ebert, Corinne M Augusto, Ann Sipe, Nelli Horvath, Jennifer E Nyland

Abstract read
In one paragraph

Article in Neurotoxicology and teratology. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Distinct medical and substance use histories associate with cognitive decline in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Sara L Mills-HuffnagleThe Pennsylvania State University College of Medicine, Department of Neural and Behavioral Sciences, 500 University Drive, Hershey, PA 17033, United States of America. Electronic address: smills1@pennstatehealth.psu.edu.
Charles N ZawatskyThe Pennsylvania State University College of Medicine, Department of Neural and Behavioral Sciences, 500 University Drive, Hershey, PA 17033, United States of America.
Gjhvona BryantThe Pennsylvania State University College of Medicine, Anatomy Graduate Program, 500 University Drive, Hershey, PA 17033, United States of America.
Michael EbertThe Pennsylvania State University College of Medicine, Anatomy Graduate Program, 500 University Drive, Hershey, PA 17033, United States of America.
Corinne M AugustoThe Pennsylvania State University College of Medicine, Department of Neural and Behavioral Sciences, 500 University Drive, Hershey, PA 17033, United States of America.
Ann SipeThe Pennsylvania State University College of Medicine, Department of Neural and Behavioral Sciences, 500 University Drive, Hershey, PA 17033, United States of America.
Nelli HorvathThe Pennsylvania State University College of Medicine, Department of Neural and Behavioral Sciences, 500 University Drive, Hershey, PA 17033, United States of America.
Jennifer E NylandThe Pennsylvania State University College of Medicine, Department of Neural and Behavioral Sciences, 500 University Drive, Hershey, PA 17033, United States of America.

Funding

NRSA Training CoreTL1TR002016 · NCATS · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI THOMAS, GAIL D. · 2016 to 2025
$3.4M
Immune and neuroendocrine mediators of sex-differences in pain following traumatic burn injuryR35GM146774 · NIGMS · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI Jennifer E. Nyland · 2022 to 2026
$2.2M
Evaluation of inflammation in the locus coeruleus during physical withdrawal symptoms and cognitive development in a rat model of neonatal opioid withdrawal syndrome (NOWS)F31DA059237 · NIDA · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI MILLS-HUFFNAGLE, SARA LYNN · 2023 to 2024
$76k
NCATS NIH HHS TL1 TR002016NIDA NIH HHS F31 DA059237NIGMS NIH HHS R35 GM146774
6 · The paper itself

Abstract

introductionOpioid use during pregnancy and subsequent neonatal opioid withdrawal syndrome (NOWS) have been associated with poor developmental outcomes including cognitive functioning. Less is known about the underlying molecular effects of prenatal opioid exposure and subsequent withdrawal; however, given the recent increase in NOWS cases, there is a pressing need to better understand these effects, which may partially explain cognitive deficits that have been observed in both preclinical NOWS models and patients with NOWS. This study evaluated the effects of prenatal heroin exposure and subsequent precipitated withdrawal symptoms on microglial reactivity in the nucleus accumbens (NAc), dorsal hippocampus (HC), and ventral tegmental area (VTA) in rat neonates, as well as cognitive functioning at three developmental time points using the Morris Water Maze (MWM) task.

methodsHeroin or saline (2 mg/kg) was randomly assigned and administered to six pregnant Sprague Dawley rat dams via osmotic minipump. A total of 63 rat neonates underwent naloxone-precipitated (5 mg/kg, subcutaneous injection) withdrawal testing at postnatal day 10 (PN10). Following withdrawal testing, neonates were randomly assigned to undergo perfusion and subsequent immunohistochemistry experiments to fluoresce Iba-1 for microglia detection, or to undergo the MWM task at three separate developmental time points (PN21-23; PN37; PN60) for cognitive testing.

resultsResults suggest that in-utero heroin exposure led to an increase in ultrasonic vocalizations during naloxone-precipitated withdrawal; a sensitive index of withdrawal in rat neonates. Additional results suggest increased microglial reactivity in the HC and VTA, but not the NAc, as well as reduced performance during the MWM in the group exposed to heroin in-utero. DISCUSSION: Together, these data suggest that in-utero opioid exposure is associated with microglial reactivity in brain regions associated with learning and memory, and may be associated with later cognitive deficits. Further research is needed to characterize these findings, which may inform future therapeutic strategies for this vulnerable population.

Indexed as

CognitionHeroinMicrogliaPrenatal Exposure Delayed EffectsRats, Sprague-DawleyAnimalsAnimals, NewbornFemaleHippocampusMalePregnancyRatsSubstance Withdrawal SyndromeVentral Tegmental AreaHeroinCognitive functioningMicroglia reactivityNeonatal opioid withdrawal syndromePrenatal heroin exposure

Identifiers

PMID39182528
PMCPMC11403577

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.