Sleep restriction during opioid abstinence affects the hypothalamic-pituitary-adrenal (HPA) axis in male and female rats

Abstract

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.

Keywords:

• Oxycodone
• abstinence
• sleep
• ACTH
• corticosterone
• vasopressin

Acknowledgements

This report is in honor of the memory of Mary Dallman with whom one of us (HR) trained. We thank the contributors to this study: Rachel Jackson, Madison Kruk, and Nicholas Pucek (animal experimentation and preliminary data analyses), Jonathan Phillips (hormone assays and brain processing), Ashley Gehrand (PCR), and William Cullinan (brain processing).

Disclosure statement

Hershel Raff is a Consultant for Corcept Therapeutics and Cerium Pharmaceuticals. The other authors have nothing to declare.

Data availability statement

All data generated or analyzed during this study are included in this published article or in the supplementary files in the data repository cited in the references.

Additional information

Funding

Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number [R01HL150523]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was also supported in part by the Advocate Aurora Research Institute.