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Hypothalamic-pituitary-adrenal (HPA) axis dynamics are disrupted by opioids and may be involved in substance abuse; this persists during withdrawal and abstinence and is associated with co-morbid sleep disruption leading to vulnerability to relapse. We hypothesized that chronic sleep restriction (SR) alters the HPA axis diurnal rhythm and the sexually dimorphic response to acute stressor during opioid abstinence. We developed a rat model to evaluate the effect of persistent sleep loss during opioid abstinence on HPA axis dynamics in male and female rats. Plasma ACTH and corticosterone were measured diurnally and in response to acute restraint stress in rats Before (control) compared to During subsequent opioid abstinence without or with SR. Abstinence, regardless of sleep state, led to an increase in plasma ACTH and corticosterone in the morning in males. There was a tendency for higher PM plasma ACTH during abstinence in SR males (p = 0.076). ACTH and corticosterone responses to restraint were reduced in male SR rats whereas there was a failure to achieve the post-restraint nadir in female SR rats. There was no effect of the treatments or interventions on adrenal weight normalized to body weight. SR resulted in a dramatic increase in hypothalamic PVN AVP mRNA and plasma copeptin in male but not female rats. This corresponded to the attenuation of the HPA axis stress response in SR males during opioid abstinence. We have identified a potentially unique, sexually dimorphic role for magnocellular vasopressin in the control of the HPA axis during opioid abstinence and sleep restriction. [ABSTRACT FROM AUTHOR]

• Rats self-administered oxycodone, then underwent sleep restriction or control procedures, then were tested for drug seeking. • Sleep restriction did not affect oxycodone seeking in male or female rats. • In female rats, pain-related phenotypes were related to high levels of drug seeking during the initial extinction session. • In male rats, lower anxiety-like behavior in the open field was associated with greater drug seeking. During opioid use and abstinence, sleep disturbances are common and are thought to exacerbate drug craving. In this study, we tested the hypothesis that sleep restriction during abstinence from oxycodone self-administration would increase drug seeking during extinction and footshock reinstatement tests. We also performed behavioral phenotyping to determine if individual variation in responses to stressors and/or pain are associated with oxycodone seeking during abstinence, as stress, pain and sleep disturbance are often co-occurring phenomena. Sleep restriction during abstinence did not have selective effects on oxycodone seeking for either sex in extinction and footshock reinstatement tests. Some phenotypes were associated with drug seeking; these associations differed by sex and type of drug seeking assessment. In female rats, pain-related phenotypes were related to high levels of drug seeking during the initial extinction session. In male rats, lower anxiety-like behavior in the open field was associated with greater drug seeking, although this effect was lost when correcting for oxycodone intake. Adrenal sensitivity prior to oxycodone exposure was positively associated with footshock reinstatement in females. This work identifies sex-dependent relationships between HPA axis function and opioid seeking, indicating that HPA axis function could be a therapeutic target for the treatment of opioid use disorder, with tailored approaches based on sex. Sleep disturbance during abstinence did not appear to be a major contributing factor to opioid seeking. [ABSTRACT FROM AUTHOR]