Tolulope J Ajanaku^1,2, Eamonn P. Duffy^1,2 , Jonathon O. Ward³, Luanne H. Hale³, Caleb I. Hodges³, Laura M. Saba⁴, Marissa A. Ehringer^1,2, Ryan K. Bachtell^2,3

Prescription opioid use is limited by the development of analgesic tolerance and opioid‑induced hyperalgesia (OIH), yet the extent to which these adaptations are shaped by genetic background versus drug exposure remains unclear. Here, we used 20 inbred Hybrid Rat Diversity Panel (HRDP) strains to quantify strain differences in baseline thermal sensitivity, oxycodone analgesia, the development of tolerance, and OIH following voluntary oxycodone self‑administration. Rats completed a tail immersion test before (Pre‑SA, before self‑administration) and after (Post‑SA, after self‑administration) intravenous oxycodone or saline self‑administration. Analgesia was summarized as the area under the withdrawal‑latency curve, with tolerance defined as the change in area under the curve between trials. Heritability was estimated from the mixed‑effects models of various phenotypes. Baseline and post‑exposure analgesia and thermal sensitivity were moderately heritable (H² ≈ 0.24–0.30), whereas tolerance and change in thermal sensitivity showed much lower heritability (H² ≤ 0.10), indicating a larger contribution of non‑genetic factors to these adaptations. Most strains exhibited classic tolerance to oxycodone, but a few showed sensitization or resistance. Most strains also displayed increased thermal sensitivity after oxycodone self‑administration, indicative of OIH. Surprisingly, total oxycodone intake was only weakly related to tolerance at both individual‑ and strain‑mean levels, suggesting that the mechanisms regulating oxycodone consumption and those governing analgesic tolerance are at least partly dissociable. Together, these findings indicate that opioid analgesia and baseline pain sensitivity are strongly shaped by genetic background, whereas tolerance and OIH that emerge following volitional oxycodone intake are less heritable and loosely related to total drug exposure.

1Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

2Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA

3Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO,

USA

4Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical

Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA