Long-term alcohol consumption can lead to a condition called alcoholic neuropathy, which causes uncomfortable nerve damage. Additionally, individuals struggling with alcohol addiction often experience a heightened sensitivity to pain, known as allodynia, during the withdrawal process.

Recently, researchers created a new mouse model to study cases of allodynia and alcohol-induced neuropathic pain, and found that both conditions activated microglia (a type of immune cell) within the spinal cord tissue. However, the inflammatory pathways involved in these two types of pain are distinct. These results have the potential to pave the way for targeted treatments for withdrawal-related allodynia and alcohol-induced neuropathic pain. 

As per the National Survey on Drug Use and Health, 29.5 million individuals aged 12 years and older suffered from alcohol use disorder, which is also referred to as alcohol dependency, alcohol addiction, or alcohol abuse, in the year 2021. Such individuals face difficulties in controlling or stopping their alcohol intake despite the adverse effects it has on their health, work, and relationships.

More than 50% of those who face this disorder live with constant distressful pain. Women are more susceptible to this phenomenon, with around 60% affected, while men face such challenges in only 50% of cases. According to research, this chronic use of alcohol can lead to long-lasting nerve damage, referred to as alcoholic neuropathy. Moreover, during alcohol withdrawal, such individuals feel the condition referred to as allodynia, meaning that an otherwise painless stimulus results in pain or discomfort. 

The complexity of understanding how alcohol misuse leads to pain arises from the fact that pain not only signifies alcohol misuse, but it can also be a significant cause of increased alcohol consumption. Drinking alcohol to alleviate pain has been acknowledged for a considerable period, and many people attest to using alcohol to manage or lessen their discomfort.

According to studies, alcohol has the capacity to diminish pain and can alleviate hyperalgesia, an elevated sensitivity to pain, even with small amounts that don’t intoxicate. Currently, the physiological mechanisms that trigger long-term pain related to alcohol abuse remain unknown. 

Dr. Vittoria Borgonetti, a postdoctoral researcher, and her colleagues at Scripps Research conducted a study to understand the reasons behind neuropathic pain caused by alcohol consumption and allodynia due to withdrawal. The study observed pain levels in mice that were dependent on alcohol, moderately drinking but not dependent mice, and mice that had never been exposed to alcohol. 

The study examined how alcohol impacts the immune system by experimenting on adult male and female C57BL/6J mice. The research team created three groups of mice: the control group, which had no prior contact with alcohol, the non-dependent group, which could choose between drinking water or alcohol and represented moderate drinkers, and the dependent group, which were exposed to ethanol vapor followed by withdrawal periods and modeled those with alcohol use disorder. 

The scientists measured allodynia in mice at particular intervals, using von Frey filaments, which are a collection of nylon fibers with varying thicknesses and lengths that are calibrated. The filaments apply pressure to the hind paw’s skin. By identifying the lowest force required to produce a withdrawal response, the researchers could evaluate the degree of allodynia. 

The researchers analyzed the activation of the immune response in non-dependent mice that had neuropathic pain, considering that previous studies have revealed the activation of the immune system in response to peripheral alcohol neuropathy. They utilized the technique of immunoblotting to assess the quantities of different protein molecules associated with the immune response in the spinal cord tissues of all mice. 

The consumption of alcohol causes immune cells in the spinal cord to become active. In the study, mice that were dependent on alcohol were found to have a significantly higher drinking behavior than the non-dependent group. The dependent group experienced allodynia during a 72-hour withdrawal period, but this pain was relieved as soon as they were allowed to consume alcohol again.

Interestingly, even some of the non-dependent mice display symptoms of allodynia. In mice experiencing alcohol withdrawal-related allodynia and alcohol-induced neuropathic pain, researchers observed increased levels of IBA-1 and CSF-1 in the spinal cord tissue, which suggests that microglia in the spinal cord tissue were activated. 

In mice experiencing allodynia due to alcohol withdrawal, IL-6 levels and ERK44/42 activation were found to be higher. This was not the case for mice with alcohol-induced neuropathic pain. 

The importance of these findings lies in the fact that until now, the inability to create animal models of nerve pain caused by alcohol has hindered the exploration of the underlying mechanisms leading to such pain in people with alcohol addiction. However, with this study, a preclinical model of alcohol-induced nerve pain and sensitivity has been established in mice, using chronic exposure to ethanol vapor. This model is expected to allow for further investigation in this field. 

Furthermore, the research provides insight into the routes that contribute to the development of allodynia caused by alcohol withdrawal and neuropathic pain induced by alcohol consumption. Both types of pain exhibited significant microglia activation in the tissue of the spinal cord. However, the occurrence of alcohol withdrawal-related allodynia was linked with elevated IL-6 expression and ERK44/42 activation, which was not observed in cases of alcohol-induced neuropathic pain. This illustrates that the inflammatory pathways tend to differ, which may pave the way for the creation of specific treatments in forthcoming times.