Adolescent morphine induces emotional signs of withdrawal paired with neurotoxicity selectively in male rats: Female resilience

This study evaluated the immediate and persistent behavioral and molecular consequences (i.e., emotional signs emerging during withdrawal and signs of neurotoxicity) following adolescent morphine exposure with a sex perspective. Basally, and prior to drug treatment, adolescent female rats showed smaller body weight and lower pain threshold than their male counterparts. Adolescent morphine treatment induced some sex-specific differences, while morphine impaired normal weight gain in male rats, no effects were observed for female rats. Plus, morphine produced an attenuated antinociceptive response in female rats. Moreover, following adolescent morphine treatment some emotional signs of withdrawal emerged exclusively in male rats in conjunction with signs of neurotoxicity, while female rats were not affected. In particular, an anxiolytic-like effect in adolescence during early withdrawal was followed by the development of a depressive-like phenotype (i.e., behavioral despair, anxiety-like behavior and anhedonia) in adulthood during prolonged withdrawal and paired with decreased contents of neurofilaments proteins in the prefrontal cortex. In conclusion, morphine administration during adolescence induced persistent changes in negative affect and brain toxicity selectively in male rats, suggesting female rats were resilient to these harmful effects. Given the widespread availability and use of opiate-based painkillers, the interplay between addiction, analgesia and emotional behaviors, and since adolescents and young adult humans are the age group with the highest abuse potential, these results add to the current literature by reporting distinct sex-specific opioid actions when administered in adolescence.