Fig. 4: Differential vulnerability to oxycodone addiction-like behaviors in HS rats.

A Oxycodone infusions during short-access (ShA; 2 h/day) and long-access (LgA:12/day) self-administration in resilient, mild, moderate, and severe groups (***p < 0.001). B Motivation assessed by progressive ratio (PR) testing post- ShA and post-LgA, showing infusions per session (***p < 0.001 vs ShA, #p < 0.05 and ###p < 0.001 vs immediate lower group). C Tolerance to oxycodone’s analgesic effects measured by tail immersion test at baseline (BSL), pre-ShA (15 min post-oxycodone, 150 μg/kg/infusion × 2), and post- LgA (12 h withdrawal, post-oxycodone). Data show tail withdrawal (***p < 0.001 vs BSL and ###p < 0.001 vs Oxy-pre-SA, @p < 0.05 vs immediate lower group). D Withdrawal-induced hyperalgesia assessed by von Frey test, expressed as percent change in paw withdrawal force from baseline at 10–12 h post-LgA (***p < 0.001 vs BSL; #p < 0.05, ##p < 0.01, and ###p < 0.001 vs. immediate lower group). E Linear regression analysis correlating baseline oxycodone-induced analgesia (tail immersion) with the final Addiction Index for all subjects (n = 542). Each dot represents an individual animal. The analysis reveals a highly significant positive correlation (r = 0.2426, p < 0.0001), identifying high initial physiological sensitivity as a risk factor for the development of the severe addiction phenotype.