Summary: Chronic alcohol consumption may increase pain sensitivity through two molecular mechanisms. The researchers also identified new potential drug targets for the treatment of alcohol-related chronic pain. More than half of people with alcohol use disorder (AUD) suffer from persistent pain, including alcoholic neuropathy. The study found that alcohol withdrawal could lead to neuropathy that was not reversed by reexposure 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 consumption and the other by alcohol withdrawal. This is a new finding from scientists at Scripps Research on the complex links between alcohol and pain.
The research, published in the British Journal of Pharmacology on April 12, 2023, also suggests new potential 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 dependence,” says lead author Marisa Roberto, PhD, Schimmel Family Chair in Molecular Medicine and professor of neuroscience. at Scripps Research. “Pain is both a common symptom in patients with alcohol dependence, as well as a reason why people are driven to drink again.”
Alcohol use disorder (AUD), which encompasses the conditions commonly referred to as alcohol abuse, alcohol dependence, and alcohol dependence, 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 certain cancers.
Among the many impacts of long-term alcohol use is pain: more than half of people with AUD experience persistent pain of one type or another. This includes alcoholic neuropathy, which is nerve damage that causes chronic pain and other symptoms.
Studies have also shown 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. Additionally, during withdrawal, people with AUD may experience allodynia, in which a harmless stimulus is perceived as painful.
Roberto and his colleagues wanted to know 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 dependent on alcohol (heavy drinkers), animals that had limited access to alcohol and were not considered dependent (moderate drinkers ) and those who had never drunk 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 were not alcohol dependent also showed signs of increased pain sensitivity during alcohol withdrawal but, unlike the dependent mice, this neuropathy was not reversed. by re-exposure to alcohol.
When Roberto’s group then measured inflammatory protein levels in the animals, they found that while inflammation pathways were elevated in dependent and non-dependent animals, specific molecules were only increased in dependent mice. . This indicates that different molecular mechanisms can lead to both types of pain. It also suggests which inflammatory proteins may be useful as drug targets for alcohol-related pain.
“These two types of pain vary widely, 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, postdoctoral associate at Scripps Research.
Roberto’s group is continuing to study how these molecules could be used to diagnose or treat alcohol-related chronic pain.
“Our goal is to uncover potential new molecular targets that can be used to distinguish between these types of pain and potentially be used in the future for the development of therapies,” says co-lead author Nicoletta Galeotti, PhD, associate professor of preclinical pharmacology at the University of Florence.
In addition to Roberto, study authors, “Chronic alcohol-induced mechanical allodynia by promoting neuroinflammation: a predictive mouse model of alcoholic neuropathy,” include Amanda Roberts, Michal Bajo, and Vittoria Borgonetti of Scripps Research ; and Nicoletta Galeotti from the University of Florence.
Funding: 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 Main animal model facility at the Scripps Research Institute.
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Source: Scripps Research Institute
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“Chronic alcohol-induced mechanical allodynia by promoting neuroinflammation: a predictive model of alcoholic neuropathy in mice” by Marisa Roberto et al. British Journal of Pharmacology
Alcohol-induced chronic mechanical allodynia by promoting neuroinflammation: a predictive mouse model of alcoholic neuropathy
Context and objective
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. Thus, our objective was to evaluate the development of chronic pain in a mouse model of alcohol dependence and to study the role of neuroinflammation in this chronic condition.
We used the CIE-2BC paradigm of two-bottle choice of chronic intermittent ethanol that generates three groups: (1) alcohol-dependent mice that exhibit increasing alcohol consumption, (2) non-dependent mice, mimicking moderate drinking, voluntarily drinking, and (3) alcohol-naive control male and female mice. We measured mechanical allodynia using von Frey filaments during weaning and after the last voluntary consumption. Finally, we used immunoblotting to assess 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 regulation. kinase 1/2 (ERK44/42) in spinal cord tissue of addicted and non-addicted animals.
We found a significant increase in alcohol consumption in the addicted group in both men and women compared to the nonaddicted group. The dependent group developed strong mechanical allodynia during 72 h of withdrawal, which completely reversed immediately after voluntary consumption. Furthermore, we observed an increase in pain hypersensitivity (allodynia) compared to the naïve 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 of mice related to hypersensitivity-abstinence and alcohol-neuropathy, and increased expression of IL -6 and ERK44/42 activation in mice with abstinence-related hypersensitivity, but not in mice with alcohol-induced neuropathic pain.
Conclusions and implications
We have shown that the CIE-2BC model induces two distinct pain conditions specific to the type of ethanol exposure: abstinence-related hypersensitivity in addicted mice and alcohol-induced neuropathic pain in approximately the half of the nondependent mice.