Repeated exposure to sucrose for procedural pain in mouse pups leads to long-term widespread brain alterations

Abstract

Oral sucrose is administered routinely to reduce pain of minor procedures in premature infants and is recommended as standard care in international guidelines. No human or animal studies on effects of early repeated sucrose exposure on long-term brain development have been done in the context of pain. We evaluated the effects of repeated neonatal sucrose treatment before an intervention on long-term brain structure in mouse pups. Neonatal C57Bl/6J mice (n = 109) were randomly assigned to one of 2 treatments (vehicle vs sucrose) and one of 3 interventions (handling, touch, or needle-prick). Mice received 10 interventions daily from postnatal day 1 to 6 (P1-6). A dose of vehicle or 24% sucrose was given orally 2 minutes before each intervention. At P85-95, brains were scanned using a multichannel 7.0 T MRI. Volumes of 159 independent brain regions were obtained. Early repetitive sucrose exposure in mice (after correcting for whole brain volume and multiple comparisons) lead to smaller white matter volumes in the corpus callosum, stria terminalis, and fimbria (P < 0.0001). Cortical and subcortical gray matter was also affected by sucrose with smaller volumes of hippocampus and cerebellum (P < 0.0001). These significant changes in adult brain were found irrespective of the type of intervention in the neonatal period. This study provides the first evidence of long-term adverse effects of repetitive sucrose exposure and raises concerns for the use of this standard pain management practice during a period of rapid brain development in very preterm infants.

Long-term effects of neonatal pain

“…Following repeated needle insertion in neonatal mice (10 per day on alternate forepaws and hindpaws from P1 to P6), ex-vivo magnetic resonance imaging in adulthood found no difference in regional brain volumes between needle insertion and handling groups. However, repeated sucrose administration produced significant changes in the volume of multiple brain regions (including the hippocampus) that were exacerbated by concurrent needle prick (including somatosensory cortex, thalamus and periaqueductal gray) [44]. Functionally, repeated needle insertion has been associated with age-dependent variations in hypothalamic-pituitary-adrenal axis function and stress responsivity (as also reported in preterm ex-NICU infants) and impaired spatial memory retention in adult rats [40].…”

The Energy Costs of Prematurity and the Neonatal Intensive Care Unit (NICU) Experience

“…Acutely, a single dose of oral sucrose administration for heel lance has been associated with increased ATP utilization and oxidative stress [ 10 ], perhaps due to the high metabolic cost of the fructose moiety of sucrose [ 104 ]. In a mouse pup model, the effects of early repeated sucrose treatment before an intervention on long-term brain structure was examined [ 95 ]. These mice pups received an oral dose of vehicle (sterile water) or 24% sucrose via a micropipette, two minutes before an intervention.…”

Adverse Behavioral Changes in Adult Mice Following Neonatal Repeated Exposure to Pain and Sucrose

“…However, in one of those studies, neonatal sucrose and pain exposure were induced over far longer periods than would be developmentally relevant as a model of preterm NICU care (Nuseir et al, 2015). Using a mouse model of pain and sucrose administration which closely mimics the exposure of preterm infants in the NICU, we previously reported widespread long-term alterations in white and gray matter brain volumes in adult mice repeatedly exposed to sucrose compared to water in the first week of life (Tremblay et al, 2017b). In that study, irrespective of pain exposure, repetitive sucrose induced smaller brain volumes mainly in white matter regions of the forebrain, cerebellum, and hippocampus.…”