Sex-specific biobehavioral interactions between persistent inflammatory pain and fentanyl self-administration

Chronic pain is a global health crisis that markedly reduces quality of life and is highly co-morbid with negative affective disorders and substance use disorders, including opioid use disorder (OUD). Although pain relief is a primary reason for initiating opioid use, pain management remains limited for individuals undergoing OUD treatment. The reciprocal interactions among pain, negative affect, and opioid use are not well understood, underscoring the need for preclinical models that integrate these domains. This study examines sex-specific patterns of intravenous fentanyl self-administration (IVSA) in mice with persistent inflammatory pain induced by complete Freund’s adjuvant (CFA). Animals underwent either short-access (ShA; non–dependent-like) or long-access (LgA; dependent-like) IVSA paradigms one week following the onset of CFA. Preliminary findings reveal that persistent inflammatory pain differentially alters fentanyl intake depending on sex and access condition: CFA-treated LgA females and CFA-treated ShA males show escalated fentanyl intake compared to non-pain controls. Pain also modulates the microstructure of drug taking. Females exhibit more and larger bouts with shorter inter-bout intervals than males, and this is further exacerbated by CFA. Ongoing work is assessing nociceptive (von Frey, cold plate) and affective (nest building, sucrose splash) behaviors at baseline and after IVSA to delineate how pain and negative affect contribute to fentanyl use. Additional studies will test the hypothesis that sex-specific, pain-induced escalation is mediated by increased central glucocorticoid signaling. Together, these studies aim to clarify how chronic pain shapes fentanyl use across biological sex and dependence state, and to identify glucocorticoid receptor signaling as a potential therapeutic target for OUD in the context of chronic pain. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.