Abstract
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 (ETA and ETB) 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 ETA and ETB 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.
Highlights
Preterm neonates in the Neonatal Intensive Care Unit (NICU) are subjected to many essential but painful procedures [1]
Morphine in association with caffeine is routinely used in the NICU [6, 7]; there are conflicting reports surrounding morphine analgesia and its long-term neurologic effects in preclinical and clinical studies
A clinical study has shown an association between neonatal low-dose morphine analgesia and early alterations in cerebral structure as well as short-term neurobehavioral problems that did not persist into childhood [20]
Summary
Preterm neonates in the Neonatal Intensive Care Unit (NICU) are subjected to many essential but painful procedures [1]. Morphine in association with caffeine is routinely used in the NICU [6, 7]; there are conflicting reports surrounding morphine analgesia and its long-term neurologic effects in preclinical and clinical studies. It has known to result in long-lasting neurochemical changes and affects hippocampal development [17, 18] Results from these studies suggest that morphine has neurotoxic effects; Zhaleh et al has shown that use of a low-dose morphine could have suppressive effects on cytotoxicity [19]. A clinical study has shown an association between neonatal low-dose morphine analgesia and early alterations in cerebral structure as well as short-term neurobehavioral problems that did not persist into childhood [20]. The objective of this study was to determine the effects of morphine and caffeine, independently and in combination on mitochondrial dysfunction (Drp and Mfn2), neural apoptosis (Bcl-2, Bax, and cell damage) and endothelin (ET) receptors (ETA and ETB) in neonatal rat brain
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