Adolescent Oxycodone Exposure Boosts Adult Opioid Self-Administration in Female Mice

Adolescent exposure to the painkiller oxycodone appears to leave a lasting mark on how the brain responds to opioids later in life, but the effects differ sharply between the sexes, according to a new mouse study from researchers at the University of Pennsylvania. The work, published in Frontiers in Behavioral Neuroscience, combined behavioral testing with gene-expression profiling to probe how early drug exposure shapes vulnerability to opioids in adulthood.

In the study, adolescent male and female mice were exposed to either oxycodone or saline; the author list includes Anna Keen Leonard as first author and Elizabeth A. Heller as corresponding author. As adults, the mice were tested for intravenous self-administration of remifentanil, a potent synthetic opioid.

The behavioral results were strikingly sex-specific. Adolescent oxycodone exposure increased adult remifentanil self-administration in female mice, but not in males. The abstract notes that adolescent painkiller use predicts later-life transition to more potent opioids, but that the causal relationship and its neurobiological mechanisms are not fully understood.

The researchers performed RNA sequencing on two reward-related brain regions: the nucleus accumbens and the ventral tegmental area. Tissue was collected from adult mice that had received adolescent oxycodone or saline, with or without subsequent remifentanil self-administration.

Perhaps unexpectedly, adolescent oxycodone produced only modest differences in gene expression in adulthood, although several candidate genes emerged for future study, particularly in the male nucleus accumbens. The more consistent signal appeared at the level of alternative splicing: adolescent oxycodone induced differential splicing in all comparisons examined, with a potentially greater response in the female ventral tegmental area after self-administration.

Gene-set enrichment analysis revealed distinct regional and sex-dependent patterns. In the male nucleus accumbens, adolescent oxycodone produced gene-set enrichment that was similar whether or not the animals later self-administered the opioid. In females, enrichment in this region was minimal after oxycodone alone but became substantial in the cohort that underwent self-administration. In the ventral tegmental area, the pattern was reversed: oxycodone exposure alone produced similar enrichment in both sexes, which was absent in the self-administration cohort.

Complementary rank-rank hypergeometric overlap analysis, which measures concordance in gene-expression rankings between groups, recapitulated these gene-set enrichment results, strengthening confidence in the observed patterns.

Bringing the behavioral and molecular data together, the authors propose new hypotheses rather than settled conclusions. Male mice may mount a gene-expression response in the nucleus accumbens after adolescent oxycodone that is associated with the absence of long-term increases in volitional drug taking, whereas females may rely on an alternative splicing response in the ventral tegmental area during adult self-administration that is associated with increased drug taking. The researchers emphasize that these are hypotheses generated by the study, requiring validation and mechanistic follow-up.

The study has clear limitations. It was conducted in mice, and the authors note that the causal relationship between adolescent opioid use and later potent opioid use in humans, along with its neurobiological mechanisms, is not fully understood. The gene-expression changes were described as modest, and the identified candidate genes and splicing events remain targets for future investigation. Nevertheless, by pairing a sex-specific behavioral outcome with region-specific transcriptomic signatures, the study offers a framework for understanding why adolescent opioid exposure may carry different long-term risks for males and females, and it identifies molecular entry points for that next phase of research.

Subject of Research: How adolescent oxycodone exposure affects adult opioid self-administration behavior and gene expression in male and female mice

Article Title: Effects of adolescent oxycodone exposure on adult remifentanil self-administration and gene expression in male and female mice

Article References: Leonard, A. K., Windisch, K. A., Krick, K. S., Hooks, M., Zhang, S., Blendy, J. A., & Heller, E. A. (2026). Effects of adolescent oxycodone exposure on adult remifentanil self-administration and gene expression in male and female mice. Frontiers in Behavioral Neuroscience, 20, Article 1984313. https://doi.org/10.3389/fnbeh.2026.1984313

Image Credits: AI Generated

DOI: 10.3389/fnbeh.2026.1984313

Keywords: oxycodone, adolescence, opioids, remifentanil, self-administration, RNA sequencing, nucleus accumbens, ventral tegmental area, alternative splicing, sex differences, mice, gene expression