Fentanyl Induces Cerebellar Internal Granular Cell Layer Apoptosis in Healthy Newborn Pigs

Opioids like fentanyl are regularly used in neonates for analgesia and sedation. So far, they have been reported to be safe and eligible to use. The cerebellum has become a focus of neurodevelopmental research within the last years, as it is known to play an important role in long-lasting motor, cognitive, and other behavioral changes. The cerebellar cortex is of major importance in the coordinative role of the cerebellum and highly vulnerable to injury and impaired growth.

This study was performed to evaluate the apoptotic effect of intravenous fentanyl infusion on the cerebellum in healthy newborn pigs.

Thirteen healthy pigs (n = 6) or (2) non-ventilated controls at normothermia (NTCTR, n = 7). Cerebellar sections were morphologically assessed after staining with hematoxylin-eosin. In addition, paired sections were immuno-stained for cell death [Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphate nick-end labeling (TUNEL)], and positive cells were counted in defined areas of the internal granular cell layer. In total, cells in three cerebellar gyri were counted.

We found that there was an increase in cells with apoptotic morphology in the internal granular cell layer in the NTFe group. For quantification, we found a significant increase in cell death in group (1) [median (range) number of caspase-3-positive cell group (1) 8 (1-22) vs. group (2) 1 (1-6) and TUNEL-positive cells (1) 6 (1-10) vs. (2) 1 (0-4)]. In both groups, there was no difference in the number of Purkinje cells. Both groups had comparable and stable physiological parameters throughout the 24 h period.

Twenty-four hours of continuous intravenous fentanyl infusion increased apoptosis in the internal granular cell layer in the cerebellum of healthy newborn pigs.