Study of infant rat total and regional brain volumes following repeated morphine administration
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INTRODUCTION: Physicians in the late 1980s started to recognize the harmful effects of untreated pain in infants. Opioid medications such as morphine are routinely used for sedation and treatment of pain in the youngest of patients. However, studies have found long-term sequalae to prolonged morphine administration in infancy, including smaller head circumference and increased social issues in early adolescence. Other studies on cognitive functions have produced mixed results. OBJECTIVES: To gain a better understanding of the impact of prolonged morphine administration in infancy, this study evaluated (1) total and (2) regional brain volumes in an infant rat model of prolonged morphine administration. This study also measured total body weight at the time of the MRI scan. METHODS: Rat pups received either morphine (morphine group; 10 mg/kg; n = 12 [8 females, 4 males]) or an equal volume of saline (saline group; n = 11 [6 females, 5 males]) as twice daily subcutaneous injections for the first 14 days after birth. An additional control group consisted of untreated rat pups (naïve group; n = 13 [6 females, 7 males]). Following the 14-day treatment period, structural T2-weighted brain MRI images were acquired using a 7-Tesla MRI scanner at the Small Animal Imaging Research Facility at Boston Children’s Hospital (Boston, MA). A correction for head tilt was applied by individually aligning the images in the axial and coronal planes with Freeview (Version 2.0). Total and regional brain volumes were manually extracted from ITK-SNAP (Version 3.8.0). Regions of interest included the forebrain, cortex, deep gray matter, hippocampus, cerebellum, and brainstem. Because no sex differences were noted, data were combined for each treatment group. Absolute and normalized average brain volumes as well as average body weights were compared using an ANOVA with Tukey HSD test. RESULTS: Prolonged morphine administration in the first 2 weeks of life was associated with lower body weight in comparison with saline-treated and naïve groups (F(2, 33) = 56.1, P < 0.0001). Morphine-treated pups had smaller total (F(2, 33) = 21.2, P < 0.0001) and regional absolute brain volumes for all regions analyzed in comparison with control groups. Because no differences were noted for normalized values for any of the regions analyzed, these findings suggest globally reduced brain volume. CONCLUSION: Future studies should evaluate trophic impact of prolonged morphine administration associated with smaller body weight and brain volumes in infant rats. Current data implicate global brain decrease and warrant future mechanistic studies of repeated morphine administration on brain development.