Background: The opioid overdose and opioid use disorder epidemics are concomitant with increased metabolic and CVD risk. Although opioid use disorder causes adverse pregnancy outcomes, the offspring’s cardiovascular health is understudied. We hypothesized that offspring exposed to morphine in utero would show increased CVD risk factors and endogenous opioid system dysregulation. Methods: Sprague Dawley dams were treated with saline (vehicle, n=10) or escalating doses of morphine (5–20 mg/kg per day, SC, n=10) during gestation. Cardiovascular and metabolic parameters were assessed in adult offspring. Results: Litter size and pups’ birth weight were not different in response to morphine exposure. Female and male morphine-exposed offspring showed reduced body length at birth ( P <0.05) and body weight from weeks 1 to 3 of life ( P <0.05), followed by a catch-up growth effect. By week 16, female and male morphine-exposed rats showed reduced tibia length ( P <0.05) and fat mass. In utero morphine exposure increases the mean arterial pressure and the depressor response to mecamylamine (5 mg/kg per day, IP) increases were abolished by a chronic treatment with an alpha-adrenergic receptor blocker (prazosin; 1 mg/kg per day, IP). Although circulating levels of angiotensin peptides were similar between groups, in utero morphine exposure exacerbated maximal ex vivo Ang (angiotensin) II–induced vasoconstriction ( P <0.05) and induced endothelial dysfunction in a sex-specific manner ( P <0.05). Proenkephalin, an endogenous opioid peptide that lowers blood pressure and sympathetic-mediated vasoconstriction, showed reduced mRNA expression in the heart, aorta, and kidneys from morphine versus vehicle group ( P <0.05). Conclusions: Among the effects of in utero morphine exposure, neurogenic hypertension, vascular dysfunction, and metabolic dysfunction could be associated with the dysregulation of the endogenous opioid system.
Chronic opioid exposure and opioid use disorder are associated with nearly a 2-fold increased risk of CVD and 16% increase in coronary artery disease. Opioid abuse during pregnancy increases 5 fold the incidence of neonatal opioid withdrawal syndrome (NOWS) and is associated with low birth weight; however, the effect of OUD among pregnant women on their offspring health is understudied. Previously, we have shown that both male and female offspring from dams exposed to mu-opioid receptor agonist morphine (MOR) during the whole pregnancy are smaller and display high blood pressure. This study aimed to investigate the potential underlying mechanisms associated with increased blood pressure in MOR- exposed offspring. 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, and pups were weaned on standard diet. Lipid profile was assessed as a risk factor for coronary artery disease using FPLC. MOR exposed offspring showed increased LDL (F-MOR vs. VEH ~2 fold; M-MOR vs. VEH ~1.5 fold mg/dL; n=6-8, p<0.05). Leptin levels, normalized to body fat, were not different between groups (F-MOR 219.8±35 vs F-VEH 181.4±15.8 pg/g fat; M-MOR 207.2±26.7 vs M-VEH 200.3±23.3 pg/g fat, n=7-8). Although proteinuria was not different in MOR exposed rats vs. VEH (F-MOR 4.6±0.8 vs F-VEH 5.5±1mg/ml; M-MOR 29.1±1.4 vs M-VEH 37.5±2.95 mg/mL; n=7-8), creatinine clearance was reduced in MOR-exposed males but not females (M-MOR 0.51±0.1 vs M-VEH 0.87±0.3 mL/min, n=7-8). MOR-exposed offspring showed a greater reduction in the pressor response to mecamylamine (F-MOR -46.25±6 vs F-VEH -18.3±1.3, M-MOR -50.5±0.28 vs M-VEH -25±5.1 delta mmHg, p<0.05). Proenkephalin, an endogenous opioid peptide that has been shown to inhibit the beta adrenergic receptor signaling, showed a ~3-fold reduction in heart and a ~7.5-fold reduction in the kidney cortex and outer medulla mRNA expression vs. VEH (-2ddCt, n=6-8, p<0.05). Maternal MOR exposure increases the sympathetic tone, which could be associated with increased sympathetic outflow to the kidney and the heart. Reduced proenkephalin could be involved in potential crosstalk between adrenergic and opioid receptor signaling exacerbating the actions of catecholamines.
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