Transgenerational blunting of morphine-induced corticosterone secretion is associated with dysregulated gene expression in male offspring.

A number of parental experiences, even when occurring prior to conception, have been shown to induce transgenerational effects beyond the first generation. In the case of exposure to drugs of abuse, studies in rodents suggest that offspring demonstrate significant differences in how they respond to the drug to which their parent was exposed. We have previously observed significant alterations in morphine analgesia, conditioned place preference and self-administration in the offspring of females exposed to morphine during adolescent development. In addition to effects on pain perception and reward, morphine also modulates the hypothalamic pituitary adrenal (HPA) axis. The purpose of the current study was to determine whether female adolescent morphine exposure results in transgenerational effects on regulation of the HPA axis by morphine in future generations. Adolescent morphine was administered to female Sprague Dawley rats using a 10 day, escalating dose regimen of morphine (5-25 mg/kg; from 30 to 39 days of age). Control animals received saline. Both saline and morphine exposed females (SAL-F0 and MOR-F0, respectively) were mated with drug naïve males beginning at least 3 weeks after the final injection. Plasma corticosterone levels were measured in male and female offspring (F1) during adulthood following 0, 0.1, or 10 mg/kg morphine. In addition, expression of corticotropin releasing hormone (Crh) and mu opioid receptor (Oprm1) in the paraventricular nucleus (PVN) were measured using quantitative PCR. MOR-F1 males, but not females, had blunted morphine-induced corticosterone secretion. This effect was specific to offspring from females exposed to morphine during adolescence as those exposed during adulthood produced offspring in which the effect was absent. In addition, MOR-F1 males had significantly lower levels of PVN Crh following saline. These effects were not driven by PVN oprm1 in the F1 males as there were no differences based on maternal adolescent exposure. To determine the persistence of the blunted morphine-induced corticosterone effect, SAL-F2 and MOR-F2 males were examined. Blunted morphine-induced corticosterone secretion extended into the MOR-F2 generation, as well as effects on Crh. In addition, there was additional dysregulation ofOprm1 expression in the PVN in MOR-F2 compared with SAL-F2 males. These findings suggest that sex-specific alterations in opioid-mediated regulation of the HPA axis are transgenerationally transmitted for at least two generations following female adolescent morphine exposure. These effects may play a role in the previously observed changes in morphine analgesia and reward-related behaviors observed in this phenotype. In addition, alterations in HPA functioning such as these may play a broad role in transgenerational epigenetic transmission.