In mice, being kept alone made it harder for them to recover from pain, especially in females, and lowered their blood oxytocin levels. Isolation also increased anxiety‑like behavior in both sexes. The hormone changes were different for males and females, showing that social environment and sex both shape pain and stress responses.

Chronic pain profoundly impacts mental health, and the social environment significantly modulates pain perception and emotional states. Recognizing the influence of biological sex on pain modulation, basic pain research increasingly investigates sex differences. The hyperalgesic priming protocol effectively models the neuroplastic mechanisms underlying the transition from acute to chronic pain in male and female rodents. Furthermore, accumulating evidence implicates specific hormones, including oxytocin, vasopressin, and corticosterone, in the pathophysiology of pain. This study aimed to determine the interactive influence of sex and social isolation on pain-related behaviors and plasma levels of oxytocin, vasopressin, and corticosterone in mice subjected to hyperalgesic priming. Two experiments were conducted using adult male and female mice (60-63 postnatal days). Experiment 1 assessed mechanical hypersensitivity, facial expression, and anxiety- and depression-like behaviors. In Experiment 2, following a period of social isolation, mice were euthanized, and blood samples were collected via cardiac puncture for plasma hormone analysis. Our results revealed that social isolation impaired recovery from mechanical hypersensitivity and increased facial expressions of pain, specifically in female mice. Independent of sex and hyperalgesic priming, isolation produced heightened anxiety- and depression-like behaviors. Hormonal analyses demonstrated sex-specific effects of isolation. Plasma oxytocin levels decreased upon isolation in both male and female mice. Curiously, primed isolated males showed a recovery of oxytocin levels similar to naïve mice, whereas primed isolated females maintained significantly lower oxytocin levels. Social isolation, coupled with hyperalgesic priming, also decreased vasopressin levels in females. While males displayed higher baseline vasopressin levels, isolation and/or hyperalgesic priming led to a reduction in their plasma vasopressin compared to naïve groups. Curiously, social isolation decreased of corticosterone levels in both males and females. In conclusion, our findings demonstrate that social isolation differentially modulates behavioral and hormonal responses to hyperalgesic priming in a sex-dependent manner, highlighting the complex interplay between social environment, sex, and pain chronification.