Mechanical and Heat Hyperalgesia upon Withdrawal from Chronic Intermittent Ethanol Vapor depends on Sex, Exposure Duration and Blood Alcohol Concentration in Mice

Abstract

Approximately half of patients with alcohol use disorder (AUD) report pain and this can be severe during withdrawal. However, many questions remain regarding the importance of sex, blood alcohol concentration (BAC), time course, and pain modality. To examine the impact of sex and BAC on the time course of the development of mechanical and heat hyperalgesia, we characterized a mouse model of Chronic Alcohol Withdrawal Induced Pain (CAWIP) in the presence or absence the alcohol dehydrogenase inhibitor, pyrazole. Male and female C57BL/6J mice underwent chronic intermittent ethanol vapor (CIEV) + or - 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 hr after cessation of ethanol exposure. In the presence of pyrazole, males developed mechanical hyperalgesia after the first week of CIEV 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 CAWIP develops in a sex, time, and BAC dependent manner in C57BL/6J mice.

Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: A mouse model of alcohol‐evoked neuropathic pain

“…Moreover, Brandner et al (2023) demonstrated a sex difference in hypersensitivity-state during the 4 weeks of CIE model, in which vapour exposure produced heat hyperalgesia only in female and not in male mice (Brandner et al, 2023), and the dependent mice developed a strong hypersensitivity as early as the first hours of abstinence (8-72 h). A limitation of the current work is the lack of a longer timecourse, but future studies will assess additional time points to clarify the trend over time and the resolution of hypersensitivity.…”

“…The rat models of the chronic ethanol exposure reported mechanical allodynia (Edwards et al, 2012) and hyperalgesia (Avegno et al, 2018;Roltsch Hellard et al, 2017) in the dependent male rats undergoing withdrawal. Recent mouse studies have reported sex-and time course-specific mechanical and heat hyperalgesia during the alcohol withdrawal (Brandner et al, 2023).…”