Stress reveals a specific behavioral phenotype for opioid abuse susceptibility.

Susceptibility to stress has long been considered important for the development of substance use disorders. Nonetheless, behavioral and physiological responses to stress are highly variable, making it difficult to identify the individuals who are most likely to abuse drugs. In the present study, we employed a comprehensive battery of tests for negative valence behaviors and nociception to identify individuals predisposed to opioid seeking following oral opioid self-administration. Furthermore, we examined how this profile was affected by a history of stress. We observed that mice receiving foot shock stress failed to exhibit a preference for sucrose, showed increased immobility in the forced swim task, and exhibited mechanical hypersensitivity when compared to controls. When considering these behaviors in light of future fentanyl-seeking responses, we observed that heightened mechanical sensitivity corresponded to higher opioid preference in mice with a history of stress, but not controls. Moreover, we were surprised to discover that paradoxically high sucrose preferences predicted fentanyl preference in shock mice, while signs of anhedonia predicted fentanyl preference in controls. Taken together, these results indicate that stress can act as a physiological modulator, shifting profiles of opioid abuse susceptibility depending on an individual's history.