Addiction-Like Behavioral Severity Predicts Prolonged Oxycodone Withdrawal-Induced Allodynia in Genetically Diverse...

Opioid withdrawal is associated with heightened pain sensitivity, including allodynia. Although opioid-induced allodynia is well-documented in humans and animal models, the relationship between the severity of opioid withdrawal-induced allodynia and individual addiction-like behaviors remains poorly understood. To address this gap, Heterogeneous Stock rats underwent long access (12 hours/day) intravenous oxycodone or saline self-administration, followed by measurement of mechanical sensitivity at six timepoints across three weeks of abstinence. Oxycodone self-administering rats were stratified by an Addiction Index derived from individual differences in the escalation of oxycodone intake, motivation to consume oxycodone, tolerance to oxycodone's analgesic effects, and acute opioid withdrawal-induced mechanical pain sensitivity. Here, we show that High Addiction Index rats developed significantly more intense and longer-lasting allodynia than Low Addiction Index rats, identifying High Addiction Index status as a distinct, severe phenotype within the oxycodone self-administering population. Saline self-administering rats developed allodynia comparable in magnitude to Low Addiction Index rats, further distinguishing the severe phenotype of High Addiction Index rats. Results remained consistent even when excluding allodynia from the Addiction Index, highlighting the robustness of the association between addiction-like severity and protracted allodynia. These findings demonstrate that severe addiction-like behavior, rather than opioid exposure alone, is associated with protracted abstinence-associated allodynia and identify High Addiction Index status as a distinguishing feature of vulnerability to prolonged pain during abstinence. supporting mechanical allodynia as a marker of addiction-like severity. These results motivate future work to define the mechanisms linking addiction-like severity to protracted opioid withdrawal-induced pain, with the goal of informing targeted clinical interventions for patients most susceptible to severe opioid withdrawal-induced allodynia.