Objective To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). Study design A prospective cohort of 136 very preterm neonates (24–32 weeks gestational age) was serially scanned with MRI near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Scales of Motor Development-2 and cognitive outcomes with the Bayley-III at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. Results A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P=0.04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.2% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P=0.30). Greater morphine exposure also predicted poorer motor (P<0.001) and cognitive outcomes (P=0.006) at 18 months CA, an association mediated, in part, by slower brain growth. Conclusions Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed.

Consolidated memories can become destabilized and open to modification upon retrieval. Destabilization is most reliably prompted when novel information is present during memory reactivation. We hypothesized that the neurotransmitter acetylcholine (ACh) plays an important role in novelty-induced memory destabilization because of its established involvement in new learning. Accordingly, we investigated the effects of cholinergic manipulations in rats using an object recognition paradigm that requires reactivation novelty to destabilize object memories. The muscarinic receptor antagonist scopolamine, systemically or infused directly into the perirhinal cortex, blocked this novelty-induced memory destabilization. Conversely, systemic oxotremorine or carbachol, muscarinic receptor agonists, administered systemically or intraperirhinally, respectively, mimicked the destabilizing effect of novel information during reactivation. These bidirectional effects suggest a crucial influence of ACh on memory destabilization and the updating functions of reconsolidation. This is a hitherto unappreciated mnemonic role for ACh with implications for its potential involvement in cognitive flexibility and the dynamic process of long-term memory storage.

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