In utero Morphine Exposure Increases Blood Pressure in Association with Increased Markers of Sympathetic Activation in the Adult Offspring
Authors: Ahmed Nermin , Kassis Alana , Malone Jena , Zamzani Esraa , Gong Ming , Loria Analia , Dalmasso Carolina 
Published: May 2023

The opioid overdose and opioid use disorder (OUD) epidemics are concomitant with nearly a 2-fold increased risk of cardiovascular disease (CVD). Opioid abuse during pregnancy increases the incidence of neonatal opioid withdrawal syndrome (NOWS) by 5-fold; however, the long-term effects on the offspring’s cardiovascular health are understudied. Previously, we have shown that both male and female offspring from dams exposed to mu-opioid receptor agonist morphine (MOR) during pregnancy display high blood pressure and reduced renal function as adults. Further, cardiovascular tissues of MOR-exposed offspring show downregulation of the endogenous opioid peptide proenkephalin (PENK) mRNA expression, which has been shown to play a role in modulating the adrenergic receptors signaling. This study aimed to investigate whether increased blood pressure in MOR-exposed offspring is associated with the activation of the sympathetic system.Sprague Dawley dams were treated with escalating doses of MOR (5-20 mg/kg/day, s.c) or saline (VEH) from gestational day 1 to 18. At 16 weeks, rats were implanted with femoral artery catheters for direct blood pressure measurements in response to the alpha-adrenergic receptor (A-ADR) blocker doxazosin (4 mg/kg/day, s.c) or saline. At the end of the study, plasma norepinephrine (NE) was measured by HPLC, and brain micropunches of the paraventricular nucleus of the hypothalamus (PVN), implicated in blood pressure regulation, were collected for RNAseq analysis.MOR-exposed offspring showed a greater reduction in the pressor response to mecamylamine (5 mg/kg, IP, delta change in mmHg: F-MOR -44.9±5.8 vs F-VEH -18.3±1.3, p<0.05, M-MOR -49.75±6.3 vs M-VEH-25±5.1, p<0.05, n=3-5). Doxazosin induced a 3-fold reduction in the blood pressure from MOR-exposed offspring compared to VEH (p<0.05). Additionally, plasma NE was higher in male MOR-exposed offspring vs VEH (M-MOR 326.1±58.6 vs M-VEH 173.2±36.7 ng/mL, p<0.05, n=7-8) but not in female MOR-exposed (F-MOR 96.7±13.7 vs F-VEH 140.3±16 ng/mL, p>0.05, n=6-8). Renal mRNA expression of the alpha-adrenergic receptor was downregulated ~3-fold (-2ddCt n=6-8, p<0.05) in MOR-exposed rats compared to VEH-exposed rats, suggesting desensitization of the A-ADR secondary to chronic stimulation. Furthermore, MOR-exposed offspring showed a 2-fold increase in FosB gene expression in PVN, which encodes the transcription factor DFosB that can accumulate in neurons after chronic opioid exposure.Prenatal MOR exposure is associated with a long-term increase in sympathetic activation of the offspring, which most likely plays a role in the development of hypertension and impaired renal function mediated by A-ADR. Prenatal MOR exposure may increase FosB gene expression, which may stimulate DFosB accumulation in PVN, contributing to the increased sympathetic outflow, HL135158 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.