Sex-specific Effects of Perinatal Opioids Exposure on Obesity-related Vascular Function in Rats

Abstract Sex-specific effects of perinatal opioids exposure on obesity-related vascular function in rats Opioid use disorder (OUD) is one of the greatest public health threats in the US. In 2018, more than 67,000 Americans died of a drug overdose, most commonly opioid-related. Initially, opioid overdose deaths were caused by prescription opioids (e.g., oxycodone), followed by a second wave of overdose deaths involving heroin, which is metabolized to morphine (MOR). While prescription opioids and heroin are still contributing to the opioid epidemic and overdose deaths, an alarming third wave of overdose deaths is on the rise now caused by synthetic opioids, specifically illicitly manufactured fentanyl (FEN). Reported in both human and animal models, opioid administration results in a diabetic-like metabolic state, including decreased glucose clearance, decreased insulin secretion, and alterations in glucose homeostasis and lipid profile. Pregnant women with OUD are an understudied special and vulnerable population affected by the opioid epidemic, as demonstrated by the nationwide increased incidence of neonatal abstinence syndrome (NAS), specifically neonatal opioid withdrawal syndrome (NOWS). Thus, there are concerns about the metabolic consequences of the offspring of mothers with extensive opioid exposure and opioid use disorder. In a preliminary study, we treated pregnant rats with ramping doses of MOR (s.c.) during the entire gestation period to create a pre-clinical model of extensive opioid exposure to study the cardiometabolic consequences of in utero opioid exposure. In a preliminary study, we treated dams with MOR throughout pregnancy; we found that female offspring from dams treated with ramping doses of MOR show low birth weight compared to vehicle-exposed females offspring. However, both female and male weanlings from MOR-treated dams are significantly smaller than VEH-treated dams weanlings. Interestingly, after 2 weeks of placing weanlings on high fat diet (HFD, 60% kcal from fat) similar increases in adiposity and reductions in lean mass were induced in male rats from both VEH and MOR-treated groups, contrary to female weanlings from MOR-treated dams, which were smaller and showed decreased adiposity and increased lean mass compared to VEH-treated group. In addition, fasting blood glucose is increased in MOR-treated rats than VEH-treated rats. Given the lipophilic nature of fentanyl, combined with its documented metabolic effects and its dramatic contribution to the current rise in opioid-involved overdose deaths, the overall goal of this proposal is to determine the effects of perinatal FEN exposure versus VEH on the offspring – specifically, on offspring measures of diet-induced obesity and metabolic dysfunction. This proposal was designed to test the hypothesis that FEN exposure during gestation and lactation will exacerbate diet-induced obesity and cardiometabolic risk among the offspring in a sex-specific manner. We will treat dams with VEH or FEN, randomizing their litters at weaning on either chow or HFD. In these offspring, we will determine body composition, glucose homeostasis, metabolic and lipid profile in plasma, and transcriptomics, including the expression of the opioid receptor subtypes, in liver and adipose tissue.