The present study aimed to determine whether neonatal treatment with fentanyl has lasting effects on stressed developing brain. Six-day-old rats were assigned to one of three groups (10 males/group): (1) fentanyl (incision+fentanyl), (2) saline (incision+0.9% saline), and (3) unoperated (unoperated sham). Pups with a plantar paw incision received repetitive subcutaneous injections of fentanyl or vehicle through postnatal days (PNDs) 6 to 8. A nonoperated sham group served as nonstressed control. Studies included assessment of development from PND 6 to PND 21 (growth indices and behavioral testing). Fentanyl administered twice daily for three days after surgical incision had no impact on early growth and development, as measured on PND 9, but showed a lasting impact on later growth, enhanced behavioral development, and lower anxiety, as measured through PNDs 10–21. While this does not completely support a benefit from such treatment, our findings may contribute to support the neonatal use of fentanyl, when indicated, even in premature newborns. 1. Introduction Fentanyl, a potent μ-opioid agonist, is a synthetic drug that has been widely used for pain management [1, 2] and as a general anesthetic for surgical procedures in pediatrics [3–5], namely in surgical neonatal intensive care units. In a previous study, fentanyl was identified as being within the 5 medications with the highest exposure rates in a pediatric intensive care unit [2]. Fentanyl is an appropriate medication that has rarely been linked to significant adverse effects on the central nervous system (CNS) or other systems, with proper monitoring [6]. However, concerning fentanyl use in pediatric critical care population, this is one of the many medications which are not properly tested for pediatric use [2]. It is well documented in clinics [7] and in experimental work [8, 9] that gradual increases of standard doses of fentanyl [7], illicit fentanyl abuse [10], drug interactions [11], or individual susceptibility may lead to severe neurotoxicity and death [10]. Animal studies have also reported adverse effects. Kofke et al. [8] evaluated the neuropathological effects of fentanyl in the brain and showed that it produces limbic system brain damage in rats and that the damage occurs over a broad range of doses. In another study,？ ？regarding fentanyl effects in rat brain ischemia, Kofke et al. [9] showed that fentanyl, in both high and low doses, can exacerbate incomplete forebrain ischemia in rats. Additionally, it is well known from the literature that large-dose opioids in rats produce
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