Adolescent opioid exposure in female rats: transgenerational effects on morphine analgesia and anxiety-like behavior in adult offspring

Abstract

The use of narcotics by adolescent females is a growing problem, yet very little is known about the long-term consequences for either the user or her future offspring. In the current study, we utilized an animal model to examine the transgenerational consequences of opiate exposure occurring during this sensitive period. Female rats were exposed to increasing doses of morphine or its saline vehicle twice daily during adolescent development (postnatal days 30-40), after which they remained drug free. At 60 days of age, all females were mated and their adult offspring were tested for anxiety-like behavior and sensitivity to morphine. Specifically, offspring of adolescent morphine (MOR-F1)- or saline (SAL-F1)-exposed mothers were tested for acute locomotor responses in an open field, followed by testing of acute or chronic morphine analgesia on the hot plate. Open field testing indicated alterations in anxiety-like behavior in MOR-F1 female offspring, with effects dependent upon the stage of the estrus cycle. Hot plate testing revealed sex differences in baseline pain threshold and morphine sensitivity in all offspring, regardless of maternal exposure. However, when compared to their SAL-F1 counterparts, MOR-F1 male offspring demonstrated significantly increased sensitivity to the analgesic effects of acute morphine, and developed analgesic tolerance more rapidly following chronic morphine treatment. The findings indicate that prior opiate exposure during early adolescence in females produces sex-specific alterations of both emotionality and morphine sensitivity in their progeny.

Figure 1

Effects of early adolescent morphine treatment on anxiety-like behavior in adult offspring. Behavioral responses in a novel open field were examined for 10 min in F1 females across the estrous cycle. Data are locomotor activity (mean ± SEM; upper panel) and percent time spent in the center of the open field (mean ± SEM; lower panel) for separate groups of 6–10 animals. Met=metestrus, Di=diestrus, Pro=proestrus, Est=estrus. *p < 0.05 vs SAL-F1 within Estrous Cycle Stage.

Figure 2

Effects of early adolescent morphine treatment on baseline pain threshold in adult offspring. Untreated F1 males and females were tested daily for baseline pain threshold using the hot plate. Data are mean (± SEM) HPL (s) for the first and last day of testing for groups of 30–36 animals. *p < 0.001 vs Day 1 for within each sex condition. ^#p<0.001 vs F1 males on Day 1.

Figure 3

Effects of early adolescent morphine treatment on analgesic sensitivity to acute morphine in adult offspring. F1 males and females were treated with one of three doses of morphine and were tested for thermal pain threshold after 30 min. Data are % MPE on the hot plate (mean ± SEM) for groups of 7–9 animals. *p < 0.05 vs SAL-F1 collapsed across doses. ^#p<0.001 vs 1 mg/kg collapsed across maternal adolescent exposure condition.

Figure 4

Effects of early adolescent morphine treatment on the development of morphine tolerance in adult offspring. F1 males and females were tested for thermal pain threshold following each daily treatment with morphine (10 mg/kg). Data are percent of animals attaining 100 % MPE for groups of 8–9 animals. *p < 0.05 vs SAL-F1 on Treatment Day 4.