Peripheral Neuropathy After Chronic Alcohol Exposure in Mice: Impact of sex, total intake and duration and alcohol metabolism

Abstract

Alcohol induced peripheral neuropathy (AIPN) is a neurodegenerative disease caused by chronic alcohol intake and is associated with peripheral nerve damage and somatosensory symptoms, such as allodynia. Current treatments lack efficacy and do not target underlying pathology emphasizing the need for preclinical models of AIPN to elucidate mechanisms and novel targets. Thus, we performed a detailed characterization of a mouse model of AIPN and candidate mechanistic associations including the role of neuroinflammation and acetaldehyde. Our studies showed chronic alcohol induced mechanical and cold hypersensitivity and deficits in spontaneous behaviors in EtOH concentration-, time- and sex-dependent manners. Female mice drank more alcohol and developed more rapid and severe hypersensitivity but less robust deficits of spontaneous behaviors. The grimace test demonstrated chronic alcohol promoted spontaneous pain independent of sex. Duration of intake impacted alcohol-induced deficits in peripheral nerve electrophysiology amplitude and intra-epidermal nerve fiber density. We characterized an extensive time-course of chronic alcohol-induced neuroinflammation in the DRG and spinal cord and found significant time, sex and tissue effects. Polymorphisms of ALDH2 have been associated with alcohol-induced neuroinflammation, alcohol-related pain, and alcohol-induced peripheral neuropathy. We investigated the role of acetaldehyde, via inhibition of ALDH2, in the development of AIPN and showed that ALDH2 inhibition accelerated and exacerbated development of chronic alcohol-induced hypersensitivity in male and female mice. Overall, our studies in a well-controlled model of AIPN strongly point to neuroinflammation and inflammatory modulators such as acetaldehyde as important mechanistic targets for possible intervention in AIPN.

Transcriptomic and network analyses of an alcohol-induced peripheral neuropathy model identify putative role for histone demethylase Jmjd1c

“…Understanding the molecular genetic mechanisms driving AIPN is therefore crucial to therapeutic development. This study presents a transcriptomic analysis of a mouse model of high-dose ethanol exposure, reflecting heavy drinking in humans with AUD, that reproduces behavioral pathology seen with AIPN (Moncayo et al, 2025).…”

“…Mice were maintained on their assigned diets for four weeks prior to tissue collection. Recently, our group has shown that these ethanol concentration and duration parameters have been shown to decrease caudal nerve conduction amplitude and intraepidermal nerve fiber density in a mouse model of AIPN, and thus we used the same experimental design for the present study (Moncayo et al, 2025).…”

Transcriptomic and network analyses of an alcohol-induced peripheral neuropathy model identify putative role for histone demethylase Jmjd1c

“…Understanding the molecular genetic mechanisms driving AIPN is therefore crucial to therapeutic development. This study presents a transcriptomic analysis of a mouse model of high-dose ethanol exposure, reflecting heavy drinking in humans with AUD, that reproduces behavioral pathology seen with AIPN (Moncayo et al, 2025).…”

“…Mice were maintained on their assigned diets for four weeks prior to tissue collection. Recently, our group has shown that these ethanol concentration and duration parameters have been shown to decrease caudal nerve conduction amplitude and intraepidermal nerve fiber density in a mouse model of AIPN, and thus we used the same experimental design for the present study (Moncayo et al, 2025).…”

Transcriptomic and network analyses of an alcohol-induced peripheral neuropathy model identify putative role for histone demethylase Jmjd1c

“…Understanding the molecular genetic mechanisms driving AIPN is therefore crucial to therapeutic development. This study presents a transcriptomic analysis of a mouse model of high-dose ethanol exposure, reflecting heavy drinking in humans with AUD, that reproduces behavioral pathology seen with AIPN (Moncayo et al, 2025).…”

“…Mice were maintained on their assigned diets for four weeks prior to tissue collection. Recently, our group has shown that these ethanol concentration and duration parameters have been shown to decrease caudal nerve conduction amplitude and intraepidermal nerve fiber density in a mouse model of AIPN, and thus we used the same experimental design for the present study (Moncayo et al, 2025).…”

Transcriptomic and network analyses of an alcohol-induced peripheral neuropathy model identify putative role for histone demethylase Jmjd1c

“…Understanding the molecular genetic mechanisms driving AIPN is therefore crucial to therapeutic development. This study presents a transcriptomic analysis of a mouse model of high-dose ethanol exposure, reflecting heavy drinking in humans with AUD, that reproduces behavioral pathology seen with AIPN (Moncayo et al, 2025).…”

“…Mice were maintained on their assigned diets for four weeks prior to tissue collection. Recently, our group has shown that these ethanol concentration and duration parameters have been shown to decrease caudal nerve conduction amplitude and intraepidermal nerve fiber density in a mouse model of AIPN, and thus we used the same experimental design for the present study (Moncayo et al, 2025).…”