Approximately half of patients with alcohol use disorder report pain and this can be severe during withdrawal. Many questions remain regarding the importance of biological sex, alcohol exposure paradigm, and stimulus modality to the severity of alcohol withdrawal-induced hyperalgesia. To examine the impact of sex and blood alcohol concentration on the time course of the development of mechanical and heat hyperalgesia, we characterized a mouse model of chronic alcohol withdrawal-induced pain in the presence or absence the alcohol dehydrogenase inhibitor, pyrazole. Male and female C57BL/6J mice underwent chronic intermittent ethanol vapor ± pyrazole exposure for 4 weeks, 4 days/week to induce ethanol dependence. Hind paw sensitivity to the plantar application of mechanical (von Frey filaments) and radiant heat stimuli were measured during weekly observations at 1, 3, 5, 7, 24, and 48 hours after cessation of ethanol exposure. In the presence of pyrazole, males developed mechanical hyperalgesia after the first week of chronic intermittent ethanol vapor exposure, peaking at 48 hours after cessation of ethanol. By contrast, females did not develop mechanical hyperalgesia until the fourth week; this also required pyrazole and did not peak until 48 hours. Heat hyperalgesia was consistently observed only in females exposed to ethanol and pyrazole; this developed after the first weekly session and peaked at 1 hour. We conclude that Chronic alcohol withdrawal-induced pain develops in a sex-, time-, and blood alcohol concentration- dependent manner in C57BL/6J mice. Perspective: Alcohol withdrawal-induced pain is a debilitating condition in individuals with AUD. Our study found mice experience alcohol withdrawal-induced pain in a sex- and time course- specific manor. These findings will aid in elucidating mechanisms of chronic pain and AUD and will help individuals remain abstinent from alcohol.
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