Abstract
Background: Remifentanil, a synthetic opioid used for analgesia during cesarean sections, has been shown in ex vivo experiments to exert anti-apoptotic activity on immature mice brains. The present study aimed to characterize the impact of remifentanil on brain lesions using an in vivo model of excitotoxic neonatal brain injury.Methods: Postnatal day 2 (P2) mice received three intraperitoneal injections of remifentanil (500 ng/g over a 10-min period) or saline just before an intracortical injection of ibotenate (10 μg). Cerebral reactive oxygen species (ROS) production, cell death, in situ labeling of cortical caspase activity, astrogliosis, inflammation mediators, and lesion size were determined at various time points after ibotenate injection. Finally, behavioral tests were performed until P18.Results: In the injured neonatal brain, remifentanil significantly decreased ROS production, cortical caspase activity, DNA fragmentation, interleukin-1β levels, and reactive astrogliosis. At P7, the sizes of the ibotenate-induced lesions were significantly reduced by remifentanil treatment. Performance on negative geotaxis (P6-8) and grasping reflex (P10-12) tests was improved in the remifentanil group. At P18, a sex specificity was noticed; remifentanil-treated females spent more time in the open field center than did the controls, suggesting less anxiety in young female mice.Conclusions: In vivo exposure to remifentanil exerts a beneficial effect against excitotoxicity on the developing mouse brain, which is associated with a reduction in the size of ibotenate-induced brain lesion as well as prevention of some behavioral deficits in young mice. The long-term effect of neonatal exposure to remifentanil should be investigated.
Highlights
The potential neurotoxicity of anesthetics in the perinatal period prompted the US Food and Drug Administration (FDA) to release a drug safety communication warning in 2016 that stated, “repeated or lengthy use of general anesthetics or sedation drugs during surgeries or procedures in children younger than 3 years of age or in pregnant women during the final trimester may affect development of children’s brains” [1]
Compared to the control group, the pups injected with 50 ng/g of remifentanil exhibited only slight sleepiness, with no significant increase in latency times to return to a normal prone position
From 10 min post-injection, pups injected with 500 ng/g took significantly more time to turn over than pups injected with 250 ng/g remifentanil (p < 0.01 and p < 0.05 at 10 and 15 min, respectively), indicating a dose-dependent effect
Summary
The potential neurotoxicity of anesthetics in the perinatal period prompted the US Food and Drug Administration (FDA) to release a drug safety communication warning in 2016 that stated, “repeated or lengthy use of general anesthetics or sedation drugs during surgeries or procedures in children younger than 3 years of age or in pregnant women during the final trimester may affect development of children’s brains” [1]. It is a synthetic ultrashort-acting opioid, a potent muopioid receptor agonist, is metabolized by non-specific plasma and tissue esterases, and is unaffected by renal or liver function [7] Due to these pharmacologic properties, the use of remifentanil for the induction of general anesthesia in cesarean delivery or during labor has recently been proposed to reduce potential side effects of maternal anesthesia on the newborn, such as neonatal apnea or the need for mechanical ventilation at birth [8,9,10]. Pre-clinical studies evaluating the hyperalgesia model showed that activation of the mu-opioid receptor by remifentanil induces a phosphorylation cascade involving phosphorylation of the GluN2B subunit of the NMDA-R via protein kinase C [13,14,15,16,17]. The present study aimed to characterize the impact of remifentanil on brain lesions using an in vivo model of excitotoxic neonatal brain injury
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