Alcohol fuels pain: Study reveals link between alcohol use and chronic pain

Summary: Chronic alcohol consumption can increase pain sensitivity through two molecular mechanisms. The researchers also identified potential new drug targets for the treatment of chronic alcohol-related pain. More than half of people with alcohol use disorder (AUD) have persistent pain, including alcoholic neuropathy. The study found that alcohol withdrawal could result in neuropathy that was not reversed by re-exposure to alcohol.

Source: Scripps Research Institute

Chronic alcohol consumption can make people more sensitive to pain through two different molecular mechanisms, one driven by alcohol intake and one by alcohol withdrawal. This is a new conclusion from scientists at Scripps Research on the complex links between alcohol and pain.

The research, published inBritish Journal of Pharmacologyon April 12, 2023, also suggests potential new drug targets for the treatment of alcohol-associated chronic pain and hypersensitivity.

There is an urgent need to better understand the two-way street between chronic pain and alcohol addiction, says senior author Marisa Roberto, PhD, the Schimmel Family Chair of Molecular Medicine and professor of neuroscience at Scripps Research. Pain is both a common symptom in patients suffering from alcohol addiction and a reason people are driven to drink again.

Alcohol use disorder (AUD), which includes conditions commonly called alcohol misuse, alcohol dependence, and alcohol addiction, affects 29.5 million people in the United States according to the 2021 National Survey on Drug Use and Health. Over time, AUD can trigger the development of many chronic diseases, including heart disease, stroke, liver disease and some cancers.

Among the many impacts of long-term alcohol use is pain: More than half of people with AUD experience persistent pain of some kind. This includes alcoholic neuropathy, which is nerve damage that causes chronic pain and other symptoms.

Studies have also found that AUD is associated with changes in how the brain processes pain signals, as well as changes in how immune system activation occurs. In turn, this pain can lead to increased alcohol consumption. Also, during withdrawal, people with AUD may experience allodynia, in which a harmless stimulus is perceived as painful.

Roberto and his colleagues were interested in learning about the underlying causes of these different types of alcohol-related pain. In the new study, they compared three groups of adult mice: animals that were addicted to alcohol (excessive drinkers), animals that had limited access to alcohol and weren’t considered addicted (moderate drinkers), and those that had never been administered alcohol.

In addicted mice, allodynia developed during alcohol withdrawal, and subsequent access to alcohol significantly reduced pain sensitivity. Separately, about half of the mice that weren’t alcohol dependent also showed signs of heightened pain sensitivity during alcohol withdrawal, but unlike the addicted mice, this neuropathy was not reversed by re-exposure to alcohol.

When Robertos’ group then measured the levels of inflammatory proteins in the animals, they found that while inflammatory pathways were elevated in both the addicted and non-addicted animals, the specific molecules were increased only in the addicted mice. This indicates that different molecular mechanisms may drive the two types of pain. It also suggests which inflammatory proteins may be useful as drug targets to combat alcohol-related pain.

These two types of pain vary greatly, which is why it’s important to be able to tell them apart and develop different ways to treat each type, says first author Vittoria Borgonetti, PhD, a postdoctoral associate at Scripps Research.

Robertos’ group is continuing studies on how these molecules could be used to diagnose or treat alcohol-related chronic pain conditions.

Our goal is to unveil new potential molecular targets that can be used to distinguish these types of pain and potentially be used in future therapeutic development, says co-senior author Nicoletta Galeotti, PhD, associate professor of preclinical pharmacology at the University of Florence.

In addition to Roberto, the study authors, Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: a mouse model predictive of alcoholic neuropathy, include Amanda Roberts, Michal Bajo, and Vittoria Borgonetti of Scripps Research; and Nicoletta Galeotti of the University of Florence.

Financing: This work was supported by funding from the National Institutes of Health (The Integrative Neuroscience Initiative on Alcoholism Consortium AA013498, AA027700, AA021491, AA017447, AA006420 and AA029841), The Schimmel Family Chair, The Pearson Center for Alcoholism and Addiction Research, and The Scripps Research Institutes Animal Models Core Facility.

About this news of pain and alcohol addiction research

Author: Press office
Source: Scripps Research Institute
Contact: Press Office – Scripps Research Institute
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Original research: Access closed.
“Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: a predictive mouse model of alcoholic neuropathy” by Marisa Roberto et al. British Journal of Pharmacology

Abstract

Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: a predictive mouse model of alcoholic neuropathy

Context and Purpose

Unrelieved chronic pain is considered a key contributing factor to the maintenance of alcohol use disorder (AUD). The mechanisms responsible for the chronic pain associated with chronic alcohol consumption are still unknown. Therefore, our aim was to evaluate the development of chronic pain in a mouse model of alcohol dependence and to investigate the role of neuroinflammation in this chronic condition.

Experimental approach

We used the CIE-2BC two-bottle-choice paradigm of chronic-intermittent ethanol generating three groups: (1) alcohol-dependent mice showing increasing alcohol intake, (2) non-addicted mice, mimicking consumption moderate, experiencing voluntary consumption and (3) male and female alcohol-vessel control mice. We measured mechanical allodynia using von Frey filaments during withdrawal and after the last voluntary consumption. 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 addicted and non-addicted animals.

Key Findings

We found a significant escalation of alcohol consumption in the addicted group in males and females compared to the non-addicted group. The addicted group developed strong mechanical allodynia during 72 hours of abstinence, which was completely reversed immediately after voluntary consumption. Furthermore, we observed increased pain hypersensitivity (allodynia) relative to the aisle group in 40% and 50% of nondependent male and female mice, respectively. Increased expression of IBA-1 and CSF-1 was observed in spinal cord tissue in both alcohol-withdrawal-hypersensitivity-related and alcohol-neuropathy-related mice, and increased IL-6 expression and activation of ERK44/42 in mice with withdrawal-related hypersensitivity, but not in mice with alcohol-evoked neuropathic pain.

Conclusions and implications

We demonstrated that the CIE-2BC model induces two distinct pain conditions specific to the type of ethanol exposure: withdrawal-related hypersensitivity in addicted mice and alcohol-evoked neuropathic pain in approximately half of the non-addicted mice.