Glucocorticoid receptor antagonism reverses opioid and alcohol withdrawal-induced hyperalgesia in rats

Authors

• N Skandan
• VP Acosta
• JCM Vendruscolo
• MA McGinn
• LF Vendruscolo

Abstract

The opioid epidemic poses a significant public health challenge in the United States. At a neurobiological level, opioid use disorder (OUD) and alcohol use disorder (AUD) are associated with the overactivation of the hypothalamic-pituitary-adrenal axis, causing dysregulation of the glucocorticoid (GR) system in stress-related brain regions beyond the hypothalamus. A prominent symptom during withdrawal is hyperalgesia (enhanced nociceptive sensitivity), which may contribute to OUD and AUD. However, the role of the GR system in this context remains to be determined. We hypothesized that GR antagonism would reverse alcohol and opioid withdrawal-induced hyperalgesia in alcohol- and opioid-dependent rats. Independent cohorts of male and female Wistar rats received daily subcutaneous injections of heroin (2–6 mg/kg) to induce opioid dependence or were exposed to receive chronic, intermittent alcohol vapor to induce alcohol dependence. Mechanical and thermal sensitivity was measured during acute withdrawal. Male opioid-dependent and alcohol-dependent rats developed mechanical and thermal hyperalgesia, indicated by decreases in paw withdrawal threshold, whereas nondependent groups exhibited stable nociceptive sensitivity. Opioid-dependent female rats developed mechanical but not thermal hyperalgesia, despite receiving three times the dose of heroin than males, and alcohol-dependent females did not develop hyperalgesia. The GR antagonist mifepristone reversed thermal hyperalgesia in alcohol-dependent rats. Mifepristone reversed thermal and mechanical hyperalgesia in alcohol-dependent male rats. Mifepristone had no effect on thermal nor mechanical sensitivity in females. These findings suggest sex differences in the development of opioid and alcohol withdrawal-induced hyperalgesia and in the role of GR activity in thermal and mechanical sensitivity.

Scientific Focus Area: Neuroscience

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