Offspring with prenatal fentanyl exposure display a neurogenic impairment of the blood pressure control in a rat model using a programmable device for drug delivery during pregnancy

Previously, we demonstrated that fentanyl self-administration (50 ± 5 µg/kg/day, i.v.) during preconception and gestation increases sympathetic activation and blood pressure in adult offspring through a neurogenic mechanism. The present study was designed to test the autonomic control of the cardiorenal function in a model of prenatal fentanyl exposure (PFE) that removes the behavioral component of addiction by delivering fentanyl via programmable iPrecio pumps. Dams were implanted with pumps programmed to infuse an intravenous fentanyl dose comparable to daily self-administration intake, or an equal volume of sterile saline, throughout pregnancy. After 5 days of infusion, estrous cycling was monitored to determine mating day and gestational day 0, and pumps were refilled transcutaneously every 5 days. Maternal weight gain, pregnancy length, and litter size and morphometrics were comparable between groups. However, PFE neonates showed clear withdrawal behaviors at postnatal day 0—including curls, limb movements, locomotion, and head movements—reflected in higher global withdrawal scores (9.3 ± 0.7 vs. 17.6 ± 2.1 movements/10 min, p < 0.05). At 3 months of age, male offspring (n = 5–6/group) were placed in metabolic cages for urine collection and implanted with radiotelemetry devices. Following recovery, blood pressure was recorded continuously for 5 days. At the endpoint, endothelial function was evaluated ex vivo in thoracic aortic rings. Compared to VEH, PFE males exhibited higher systolic blood pressure (144 ± 3 vs. 159 ± 6 mmHg, p < 0.05), an exaggerated depressor response to the ganglionic blocker mecamylamine (−24 ± 2 vs. −38 ± 3 mmHg, p < 0.05), reduced RMSSD, a time-domain measure of heart rate variability (3.02 ± 0.21 vs. 2.23 ± 0.18 ms, p < 0.05), and lower creatinine clearance (1.56 ± 0.64 vs. 0.82 ± 0.45 ml/min, p < 0.05). PFE offspring also showed increased urinary norepinephrine (1125 ± 256 vs. 1843 ± 305 ng/day, p < 0.05) and proteinuria (5.12 ± 0.36 vs. 9.33 ± 1.2 mg/day, p < 0.05). In addition, PFE males displayed an amplified pressor response to fentanyl re-exposure (100 µg/kg; 18 ± 4 vs. 32 ± 3 mmHg, p < 0.05). Endothelial function and phenylephrine-induced vascular reactivity were unchanged between groups, supporting a neurogenic origin of hypertension. Together, these findings indicate that daily maternal fentanyl infusion via programmable pumps during preconception and gestation disrupts autonomic regulation of cardiorenal function and heightens sensitivity to fentanyl re-exposure in male offspring. Notably, this pump-based PFE model recapitulates the adverse cardiorenal outcomes produced by maternal fentanyl self-administration, providing a powerful approach for isolating the developmental effects of opioid exposure from addiction-related behaviors. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.