Sex-dependent Inflammatory Impact of Prenatal Opioids on the Developing Brain

This submission has open access
Submission ID :
ESPR77
Submission Type
Submission Topic
Abstract: :

Background: Prenatal opioid exposure may cause neonatal abstinence syndrome (NAS) and disrupt developing neuronal pathways in the neonatal brain. Emerging data show that opioids also exert sex-dependent effects in opioid-exposed offspring through non-neuronal pathways. Animal studies demonstrate that opioid binding with TLR4 on glial cells stimulates downstream pro-inflammatory cascades with associated up-regulation of inflammatory biomarkers. Such inflammation has been linked to: 1) brain injury, 2) reinforcement of reward/addictive behavior, and 3) deleterious effects on cognition well into adulthood. However, the impact of prenatal opioids on pro-inflammatory pathways in human neonates is unknown.


Objective: To non-invasively examine the sex-dependent inflammatory and rewarding effects of opioids on the developing neonatal brain through salivary transcriptomic profiling and structural and resting-state functional brain magnetic resonance imaging (sMRI and rsfMRI).


Methods: Clinical data and salivary samples from 16 neonates with NAS and 16 sex- and gestational-age matched controls without NAS were collected within 48 hours of birth. Samples underwent transcriptomic analysis of select pro- inflammatory genes (IL1B, IL6, TNFα, CXCL1, MCP1), an anti-inflammatory gene (IL10), as well as a key reward regulating gene (dopamine receptor type 2/DRD2)Threshold cycle (Ct) values of genes of interest were normalized against GAPDH and YWHAZ. The relative fold gene expression was calculated using the delta-delta Ct method. The expression of inflammatory genes was stratified by opioid exposure and sex. To explore the relationship between inflammation and reward signaling, inflammatory gene expression was correlated with DRD2 expression. Brain imaging was performed in a separate cohort of sex- and gestational-matched neonates with and without NAS. Relative fold gene expression data were analyzed using a t-test, the correlation was analyzed using the Pearson correlation method. Significance was set at p ≤ 0.05.


Results: Neonates with NAS had significantly higher expression of IL6 and MCP1 than non-exposed neonates (p≤0.05), with even higher expression in those requiring pharmacotherapy (p<0.05). Females with NAS requiring pharmacotherapy had significantly higher expression of IL1B, IL6, MCP1, and lower expression of IL10 than their male counterparts (Figure); the expression of IL6 and MCP1 correlated significantly with DRD2 (r=0.99, p<0.05). Four of five females with NAS had white matter hyperintensity on the sMRI; one male with NAS had a normal sMRI. The control cohort had normal sMRI (Table). Resting-state fMRI analysis is ongoing.


Conclusion: Prenatal opioid exposure may modulate the inflammatory pathways in a sex-dependent manner and reinforce reward properties through these non-neuronal pathways. Whether the inflammation process is contributory to the severity of NAS and white matter abnormalities in females with NAS remains subject to further research.

Optional insertion of tables and or figures :
If the file does not load, click here to open/download the file.
If the file does not load, click here to open/download the file.
Tufts University School of Medicine, Mother Infant Research Institute at Tufts Medical Center
Mother Infant Research Institute at Tufts Medical Center
Pediatric Radiology at Tufts Medical Center
Oregon Health and Science University
Oregon Health and Science University
Pediatric Neurology at Tufts Medical Center
Newborn Medicine at Tufts Medical Center
Mother Infant Research Institute at Tufts Medical Center

Similar Abstracts by Type

Submission ID
Submission Title
Submission Topic
Submission Type
Corresponding Author
ESPR157
Clinical Research
Original science
Aditya Chhikara
ESPR302
Epidemiology
Original science
Natasha Jouk
ESPR74
Clinical Research
Original science
Alexandra Mazo
36 hits