Abstract 030: Perinatal Paradigms Of Opioid Use To Investigate Cardiovascular Disease (CVD) Risk In Adult Offspring

Abstract

Adversity and dysfunctional households during childhood have been shown to increase systolic blood pressure and overall CVD risk in the long term. A common contributor to dysfunctional households is the parental drug abuse, which transplacental effects acts as a stressor to the developing offspring. Opioid use disorder (OUD) among pregnant women is an understudied area related to the opioid epidemic, causing a 5-fold increase in neonatal opioid withdrawal syndrome (NOWS) incidence. In former studies, we subjected female rats to two models of maternal opioid exposure 1) daily escalating doses of morphine from gestational day 1-19, or 2) fentanyl self-administration during preconception and gestation. Female and male opioid-exposed offspring are smaller throughout the lifespan than vehicle (VEH)-exposed counterparts, displaying NOWS-like somatic withdrawal signs and catch-up growth. Also, in utero opioid-exposed adult offspring displayed sympathetic activation and increased CVD risk factors. Perinatal exposure to opioids has been shown to dysregulate the endogenous opioid peptides (EOP) and alter behavioral outcomes later in life, but the effects on blood pressure regulation remain understudied. Therefore, this study aimed to investigate the expression of proenkephalin (PENK) in brain regions known to control the sympathetic outflow (PVN, RVLM, NTS) and the pressor response to Leu-Enkephalin (100 ug/kg i.p) in adult offspring exposed to VEH or opioids in utero. PENK protein expression in RVLM showed a ~50% reduction in opioid-exposed offspring vs. VEH (p<0.05). As expected, the pressor response to Leu-ENK in conscious VEH-exposed rats showed a ~30% increase in mean arterial pressure from baseline, while the pressor response was blunted in opioid-exposed offspring (12.2±3.7 vs. -4.5±2.1 delta mmHg, n=4-5, p<0.05). As EOP exert inhibitory effects on adrenergic signaling, our data indicate that perinatal exposure to opioids may induce a permanent downregulation of EOP in the central nervous system. Similar to what we reported in vasculature and heart, reduced PENK may contribute to increasing the sympathetic tone and desensitize acute pressor responses to EOP, suggesting that optimal EOP levels may be critical for blood pressure regulation.