Prenatal opioid exposure such as oxycodone is linked to significant adverse effects on the developing brain. Endothelin (ET) and its receptors are involved in normal development of the central nervous system. Opioid tolerance and withdrawal are mediated through ET receptors. It is possible that adverse effect of oxycodone on the developing brain is mediated through ET receptors. We evaluated brain ETA and ETB receptor expression during postnatal development in rats with prenatal oxycodone exposure. Timed pregnant Sprague-Dawley rats received either oxycodone or placebo throughout gestation. After birth, male rat pups were sacrificed on postnatal day (PND) 1, 7, 14 or 28. Brain ETA and ETB receptor expression was determined by Western blot analysis. Oxycodone pups compared to placebo demonstrated congenital malformations of the face, mouth, and vertebrae at the time of birth [4/69 (5.7%) vs. 0/60 (0%); respectively] and intrauterine growth retardation [10/69 (15%) vs. 2/60 (3.3%); respectively]. On PND 28, oxycodone pups compared to placebo had lower body and kidney weight. ETA receptor expression in the oxycodone group was significantly higher compared to placebo on PND 1 (p=0.035), but was similar on PND 7, 14, or 28. ETB receptor expression decreased in oxycodone compared to placebo on PND 1 and 7 (p=0.001); and increased on PND 28 (p=0.002), but was similar on PND 14. Oxycodone-exposed rat pups had lower birth weight and postnatal weight gain and greater congenital malformations. ETB receptor expression is altered in the brain of oxycodone-treated rat pups indicating a possible delay in CNS development.
Background: Preterm infants experience rapid brain growth during early post-natal life making them vulnerable to drugs acting on central nervous system. Morphine is administered to premature neonates for pain control and caffeine for apnea of prematurity. Simultaneous use of morphine and caffeine is common in the neonatal intensive care unit. Prior studies have shown acute neurotoxicity with this combination, however, little information is available on the mechanisms mediating the neurotoxic effects. The objective of this study was to determine the effects of morphine and caffeine, independently and in combination on mitochondrial dysfunction (Drp1 and Mfn2), neural apoptosis (Bcl-2, Bax, and cell damage) and endothelin (ET) receptors (ET A and ET B) in neonatal rat brain. Methods: Male and female rat pups were grouped separately and were divided into four different subgroups on the basis of treatments-saline (Control), morphine (MOR), caffeine (CAFF), and morphine + caffeine (M+C) treatment. Pups in MOR group were injected with 2 mg/kg morphine, CAFF group received 100 mg/kg caffeine, and M+C group received both morphine (2 mg/kg) and caffeine (100 mg/kg), subcutaneously on postnatal days (PND) 3-6. Pups were euthanized at PND 7, 14, or 28. Brains were isolated and analyzed for mitochondrial dysfunction, apoptosis markers, cell damage, and ET receptor expression via immunofluorescence and western blot analyses. Results: M+C showed a significantly higher expression of Bax compared to CAFF or MOR alone at PND 7, 14, 28 in female pups (p < 0.05) and at PND 7, 14 in male pups (p < 0.05). Significantly (p < 0.05) increased expression of Drp1, Bax, and suppressed expression of Mfn2, Bcl-2 at PND 7, 14, 28 in all the treatment groups compared to the control was observed in both genders. No significant difference in the expression of ET A and ET B receptors in male or female pups was seen at PND 7, 14, and 28. Conclusion: Concurrent use of morphine and caffeine during the first week of life increases apoptosis and cell damage in the developing brain compared to individual use of caffeine and morphine.
Oxidative stress results from excessive reactive oxygen species formation and/or inadequate antioxidant defense. Premature and critically ill infants are especially susceptible due to an immature intrinsic antioxidant system that cannot fully compensate for a free radical load. Oxidative stress is also associated with endothelial dysfunction and alterations in Endothelin-1 (ET-1) signaling pathways. However, the effects of the complex interaction between oxidative stress and ET-1 in newborns are not well-understood. The objective of this pilot study was to determine the relationship between levels of common oxidative stress biomarkers [glutathione (GSH), malondialdehyde (MDA)] and ET-1 in newborns of different gestational ages. In a level IV NICU, 63 neonates were prospectively enrolled and divided into groups based on gestational age at birth: Early Preterm (24 0/7-30 6/7 weeks), Late Preterm (31 0/7-36 6/7 weeks), and Term (37 0/7-42 weeks). Umbilical cord (1.5 mL) and 24(±4) h of life (24 h) (1 mL) blood samples were collected for GSH, MDA, and ET-1 analyses. GSH, MDA, and ET-1 were determined using established methodology. Mean cord MDA levels for all age groups, Early Preterm (2.93 ± 0.08 pg/ml), Late Preterm (2.73 ± 0.15 pg/ml), and Term (2.92 ± 0.13 pg/ml), were significantly higher than those at 24 h of life (p < 0.001). Mean cord ET-1 levels were significantly higher than 24 h samples in both Early and Late Preterm groups (p < 0.05). Cord and 24 h ET-1 levels did not correlate with MDA and GSH levels at birth (r 2 = 0.03, p > 0.05 and r 2 = 0.001, p > 0.05, respectively) or 24 h of life (r 2 = 0.001, p > 0.05 and r 2 = 0.03, p > 0.05, respectively). Preterm neonates exposed to prenatal corticosteroids (1.87 ± 0.31 pg/ml) had lower cord MDA levels than non-exposed neonates (2.85 ± 0.12 pg/ml) (p < 0.05). Both cord and 24 h OS markers were significantly higher in neonates treated with oxygen therapy (p < 0.005 and p < 0.05, respectively) than those who did not receive supplemental oxygen. Oxidative stress markers (MDA and GSH) and ET-1 levels act independently. MDA is higher in cord blood than at 24 h of life regardless of gestational age. In preterm neonates, ET-1 levels are higher in umbilical cord blood compared to 24 h of life.
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