Maternal morphine intake during pregnancy and lactation affects the circadian clock of rat pups.

Early-life morphine exposure causes a variety of behavioural and physiological alterations observed later in life. In the present study, we investigated the effects of prenatal and early postnatal morphine on the maturation of the circadian clockwork in the suprachiasmatic nucleus and the liver, and the rhythm in aralkylamine N-acetyltransferase activity in the pineal gland. Our data suggest that the most affected animals were those born to control, untreated mothers and cross-fostered by morphine-exposed dams. These animals showed the highest mesor and amplitude in the rhythm of Per2, Nr1d1 but not Per1 gene expression in the suprachiasmatic nuclei (SCN) and arrhythmicity in AA-NAT activity in the pineal gland. In a similar pattern to the rhythm of Per2 expression in the SCN, they also expressed Per2 in a higher amplitude rhythm in the liver. Five of seven specific genes in the liver showed significant differences between groups in their expression. A comparison of mean relative mRNA levels suggests that this variability was caused mostly by cross-fostering, animals born to morphine-exposed dams that were cross-fostered by control mothers and vice versa differed from both groups of natural mothers raising offspring. Our data reveal that the circadian system responds to early-life morphine administration with significant changes in clock gene expression profiles both in the SCN and in the liver. The observed differences between the groups suggest that the dose, timing and accompanying stress events such as cross-fostering may play a role in the final magnitude of the physiological challenge that opioids bring to the developing circadian clock.