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Prenatal Morphine Exposure Increases Cardiovascular Disease Risk and Programs Neurogenic Hypertension in the Adult
Nermin Ahmed1, Alana Kassis1, Jena Malone1
1Department of Pharmacology and Nutritional Sciences, College of Medicine (N.A., A.K., J.M., J.Y., E.Z., C.D., A.S.L.), University of Kentucky, Lexington, KY.
Insights
In utero morphine exposure (IUME) in rats leads to cardiovascular and metabolic issues in offspring, including hypertension and vascular dysfunction. These effects are linked to altered endogenous opioid system signaling, impacting offspring cardiovascular health.
Area of Science:
- Cardiovascular Science
- Developmental Biology
- Pharmacology
Background:
- Opioid use disorder and overdose epidemics are linked to increased metabolic and cardiovascular disease (CVD) risk.
- Opioid use disorder during pregnancy can negatively impact offspring health, yet their long-term cardiovascular outcomes remain understudied.
- In utero morphine exposure (IUME) is hypothesized to increase CVD risk factors and disrupt the endogenous opioid system in offspring.
Purpose of the Study:
- To investigate the long-term cardiovascular and metabolic effects of in utero morphine exposure (IUME) in offspring.
- To determine if IUME leads to dysregulation of the endogenous opioid system in offspring.
Main Methods:
- Sprague Dawley dams were exposed to saline or escalating doses of morphine during gestation.
- Cardiovascular and metabolic parameters were assessed in adult offspring.
- Gene expression of endogenous opioid peptides was analyzed in key tissues.
Main Results:
- IUME offspring exhibited reduced birth weight and body length, followed by catch-up growth, and later showed reduced tibia length and fat mass.
- IUME increased mean arterial pressure and exacerbated angiotensin II-induced vasoconstriction, with sex-specific endothelial dysfunction.
- Reduced proenkephalin mRNA expression was observed in the heart, aorta, and kidneys of IUME offspring.
Conclusions:
- IUME in rats results in neurogenic hypertension and vascular dysfunction in offspring.
- Endothelial dysfunction and metabolic changes observed in IUME offspring may be sex-specific.
- Dysregulation of the endogenous opioid system is implicated in the cardiovascular and metabolic consequences of IUME.
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 in utero morphine exposure (IUME) 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 IUME. Female and male IUME 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 IUME rats showed reduced tibia length (P<0.05) and fat mass. IUME increases the mean arterial pressure and the depressor response to mecamylamine (5 mg/kg per day, IP) induced by IUME 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, IUME 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 IUME, neurogenic hypertension, vascular dysfunction, and metabolic dysfunction could be associated with the dysregulation of the endogenous opioid system.
