Transgenerational effects of opioids on cardiovascular outcomes of the rat offspring

Abstract

Opioid use disorder (OUD) is one of the greatest public health threats in the US. In 2020, more than 69,000 Americans died of a drug overdose involving opioids. Starting in 2014, an alarming third wave is on the rise now caused by synthetic opioids, specifically illicit fentanyl (FEN). OUD among pregnant women is an understudied area related to the opioid epidemic, showing a 5-fold increase incidence of neonatal opioid withdrawal syndrome (NOWS). Currently, the only two FDA-approved medications indicated for medication assisted treatment (MAT) during pregnancy are methadone and buprenorphine. While some general guidelines have been established to place pregnant woman on MAT, the misuse of fentanyl has challenged the current pharmacotherapies, urging for the characterization of pre-clinical models.The aim of this study was to investigate the trasngenerational effects of opioids on the cardiovascular system. We subjected female rats to opioids exposure during pregnancy. We investigated: 1) In the newborns, the morphometrics and withdrawal symptoms; 2) In the adult offspring, the locomotor sensitization 3) The short and long-term plasma endogenous opioids peptides status, and 4) the transcriptomics of brain areas involved in the neural interface between motivation and action.We found that female and male neonates from opioids-treated dams are smaller through the lifespan compared to VEH-exposed counterparts (n=6, p<0.05). Also, adult offspring exposed to MOR in utero displayed sympathetic activation and increased cardiometabolic risk factors along with increased locomotor sensitization to MOR (n=4, p<0.05). In addition, we performed RNAseq analysis of the perivascular nucleolus of the hypothalamus in MOR-exposed offspring, showing increased FOSb expression (n=3 per group). ΔFosB, encoded by the fosB gene, is induced in the brain's reward regions by chronic exposure drugs of abuse and mediates sensitized responses to drug exposure.We also found that rat neonates exposed to opiods showed behavioral NOWS-like symptoms. Importantly, we found that the prenatal exposure to opioids induces a long-term dysregulation of the endogenous opioids peptides (EOP) pro-enkephalin and pro-dynorphin.Both endogenous and exogenous opioids can bind to opioid receptors, which are G-protein coupled receptors (GPCRs) that can dimerize and affect the function of other GPCRs with important neurobehavioral functions.This study provides insights regarding how opioids could affect the programming of the mechanisms regulating blood pressure control later in life. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.