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

Background and Purpose. Unrelieved chronic pain is considered a key factor contributing to the maintenance of alcohol use disorder (AUD). The mechanisms responsible for chronic pain associated with chronic alcohol consumption are still unknown. Thus, our goal was to evaluate the development of chronic pain in a mouse model of alcohol dependence and investigate the role of neuroinflammation in this chronic condition. Experimental Approach. We used the chronic-intermittent ethanol two-bottle choice CIE-2BC paradigm that generates three groups: (1) alcohol-dependent mice that exhibit escalating alcohol intake, (2) nondependent mice, mimicking moderate drinking, that experience voluntary drinking, and (3) alcohol-naïve control male and female mice. We measured mechanical allodynia using von Frey filaments during withdrawal and after the last voluntary drinking. Finally, we used immunoblotting to evaluate the protein levels of ionized calcium-binding adapter molecule-1 (IBA-1), macrophage-colony stimulating factor (CSF-1), interleukin 6 (IL-6), p38 and extracellular signal-regulated kinase 1/2 (ERK44/42) in spinal cord tissue of dependent and non-dependent animals. Key Results. We found significant escalation of drinking in the dependent group in male and female compared with the non-dependent group. The dependent group developed strong mechanical allodynia during 72 h of withdrawal, which was completely reversed immediately after the voluntary drinking. Moreover, we observed an increased pain hypersensitivity (allodynia) compared with the naïve group in 40% and 50% of non-dependent male and female mice, respectively. Increased IBA-1 and CSF-1 expression was observed in spinal cord tissue of both hypersensitivity-abstinence related and neuropathy-alcohol mice, and increased IL-6 expression and ERK44/42 activation in mice with hypersensitivity-related to abstinence, but not in mice with alcohol neuropathy. Conclusions and Implications. We showed that the CIE-2BC model induces two distinct pain conditions specific to the type of ethanol exposure: abstinence-related hypersensitivity in dependent mice and alcoholic-neuropathy in about a half of the non-dependent mice