Glucocorticoid receptor blockade reverses heroin and alcohol withdrawal-induced hyperalgesia in rats

Alcohol use disorder (AUD) and opioid use disorder (OUD) are associated with dysregulation of the hypothalamic-pituitary-adrenal axis and extrahypothalamic stress systems, including glucocorticoid receptor (GR) signaling. Hyperalgesia is defined as an increased sensitivity to nociceptive stimuli and is a prominent symptom of alcohol and opioid withdrawal, which is hypothesized to contribute to the development and persistence of AUD and OUD and heighten relapse vulnerability.

We tested the hypothesis that GR antagonism reverses hyperalgesia during both alcohol and opioid withdrawal.

Male and female Wistar rats were either made alcohol-dependent through chronic, intermittent alcohol vapor exposure or made opioid-dependent via daily, subcutaneous heroin injections (1-6 mg/kg). Mechanical and thermal nociceptive sensitivity were assessed 6-8 h into spontaneous withdrawal using the von Frey and Hargreaves tests, respectively.

In male rats, withdrawal from alcohol and heroin produced both mechanical and thermal hyperalgesia. The nonselective GR antagonist mifepristone reduced thermal and mechanical hyperalgesia in alcohol-dependent but not control male rats. Mifepristone reduced thermal but not mechanical sensitivity in heroin-dependent and control male rats. In female rats, alcohol withdrawal produced thermal but not mechanical hyperalgesia. Thermal hyperalgesia was reversed by mifepristone in female alcohol-dependent rats. In contrast, heroin withdrawal produced mechanical hyperalgesia that was insensitive to mifepristone but reversed by the selective GR antagonist miricorilant.

These findings reveal sex- and nociception modality-specific differences in alcohol and opioid withdrawal-induced hyperalgesia and highlight GR signaling as a potential therapeutic target for managing drug withdrawal-related pain.