Peripartum buprenorphine and oxycodone exposure impair maternal behavior and increase neuroinflammation in new mother rats

Abstract

7 % of pregnant people use opioids. Opioid use during pregnancy can negatively impact maternal and offspring health. Medications for opioid use disorder (MOUD), commonly buprenorphine, are the recommended treatment for opioid use disorder during pregnancy to prevent cycles of withdrawal and relapse. In addition to effects on opioid receptors, opioids have strong binding affinity to toll-like receptor (TLR) 4, an immune cell receptor, and thereby impact neuroinflammatory signaling. We have previously shown that neuroimmune alterations are important for the display of maternal behavior. Here, we used a rodent model to assess the impact of chronic peripartum opioid exposure or MOUD on maternal caregiving and neuroinflammation in the postpartum brain. Female rats were exposed to vehicle (VEH), buprenorphine (BUP) to model MOUD, or oxycodone (OXY), to model peripartum drug use, before, during, and after pregnancy. Opioid exposure reduced gestation length and maternal weight gain. Postpartum maternal caretaking behaviors, including pup retrieval, huddling and nursing, and pup-directed sniffing and licking, were reduced in opioid-exposed mothers. Following behavioral testing, tissue was collected from brain regions important for maternal caretaking, including the prefrontal cortex (PFC), nucleus accumbens (NAc), preoptic area (POA), amygdala (AMY), and periaqueductal grey (PAG). Immunofluorescent labeling showed that BUP increased astrocyte labeling, while OXY increased microglia labeling in the PAG, but not other regions. Gene expression analysis also showed regional and treatment differences in immune transcripts. BUP and OXY increased TLR4 in the PFC. BUP increased TNF in the NAc but decreased IL1β in the POA. OXY increased CD68 in the POA, and IL1β, TNF, and TLR4 in the PAG. Together, these results provide novel evidence of peripartum neuroimmune alterations following chronic opioid exposure that could be mediating maternal care deficits. This work provides a foundation to explore the extent to which modulation of neuroimmune activation may be a potential intervention for caregiving deficits in mothers exposed to opioids during pregnancy.

Keywords: Astrocyte; Buprenorphine; Maternal behavior; Maternal brain; Microglia; Neuroinflammation; Opioid; Oxycodone; Peripartum.