Peripartum opioid exposure impaired maternal behavior, increased inflammatory gene expression, and reduced perineuronal nets in the maternal brain network
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Date
2025-05
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The Ohio State University
Abstract
7% of pregnant people use opioids. Peripartum opioid use can cause preterm labor, preeclampsia, or pregnancy loss, and opioid withdrawal syndrome in infants. Opioid users are recommended to use medications for opioid use disorder (MOUD), commonly buprenorphine, rather than abstaining, to avoid withdrawal and relapse. Little research has explored the impact opioids and MOUD have on the highly-plastic maternal brain. Opioids have well-established effects on immune signaling in the brain, and we have established that neuroimmune alterations contribute to maternal behavior. Opioids may thus influence the maternal brain by shifting neuroimmune function. We used a rodent model to test how chronic peripartum opioid or MOUD impacted maternal behavior and neuroinflammatory markers. We also examined perineuronal nets (PNNs), extracellular matrix proteins that regulate neuroplasticity. PNNs fluctuate in the maternal brain, and their expression is known to be impacted by opioid exposure and immune activity. PNN fluctuation can be regulated by the action of matrix metalloproteinases (MMPs), which are proteases that can break down ECM components. Female rats were treated with vehicle (VEH), buprenorphine (BUP; 0.3mg/kg/day), or oxycodone (OXY; 10mg/kg/day) prior to pregnancy, throughout pregnancy, and in the postpartum period. We found that opioid mothers displayed deficits in maternal behavior in a pup retrieval task. PNNs were labeled via immunofluorescence across maternal brain regions including: prelimbic prefrontal cortex (plPFC), infralimbic prefrontal cortex (ilPFC), orbitofrontal cortex (OFC), motor cortex (mCTX), dorsal hippocampus (dHPC), amygdala (AMY), and periaqueductal gray (PAG). PNNs decreased in plPFC, ilPFC, OFC, CA2 subregion of dHPC, and PAG in opioid-treated mothers compared to VEH, but no differences were observed in AMY, mCTX, or CA3 and DG subregions of dHPC. Immunerelated transcripts that modulate PNNs, including IL33, MMP2, MMP9, TIMP1, and TLR2, were analyzed via qPCR. In the PFC, MMP2 increased in BUP mothers compared to VEH. In the PAG, TLR2 decreased in BUP mothers compared to VEH. No changes were detected in the AMY. These novel peripartum opioid-induced changes PNN expression and immune signaling in the PFC and PAG could contribute to changes in neural plasticity and behavioral deficits associated with peripartum opioid use, which we will examine in future work.
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Keywords
Perineuronal nets, Neuroimmune, Peripartum, Opioids, Maternal brain