Prior adolescent oxycodone exposure enhances pain sensitivity following chronic intermittent ethanol in adult female mice

The opioid crisis remains a critical public health concern, with rising rates of overdose and opioid use disorder. While opioids are effective for managing pain, both chronic use and withdrawal are associated with increased pain sensitivity. Although most prior research has focused on adults, opioid use during adolescence is common and linked to a heightened risk for developing alcohol use disorder and other forms of substance misuse. Like opioids, acute alcohol use can be analgesic, but chronic alcohol exposure and withdrawal lead to increased pain sensitivity. However, the interactive effects of adolescent opioid and adult alcohol exposure on pain remain poorly understood. In this study, we investigated whether adolescent oxycodone exposure (AOE) alters the development of mechanical and thermal sensitivity following adult chronic intermittent ethanol (CIE) vapor exposure in male and female mice. AOE alone induced transient mechanical but not thermal hypersensitivity in both sexes, which resolved within six days of cessation. In adulthood, CIE exposure induced mechanical and thermal hypersensitivity in both sexes. Importantly, a prior history of AOE prolonged CIE-induced hypersensitivity in female, but not male mice. Additionally, females with combined AOE and CIE exposure exhibited enhanced hypersensitivity in the Randall-Selitto test compared to all other groups. These findings demonstrate that AOE increases vulnerability to pain-related effects of adult CIE exposure in females. This work highlights the importance of studying poly-drug interactions across developmental windows and underscores the need to include both sexes in preclinical models of pain and substance use.