Researchers at Scripps Research have discovered that chronic alcohol consumption can increase sensitivity to pain through two distinct molecular mechanisms: one related to alcohol intake and the other to alcohol withdrawal. This finding, published in the British Journal of Pharmacology, sheds light on the intricate relationship between alcohol and pain.
The researchers sought to better understand the relationship between chronic pain and alcohol use disorder. They wanted to investigate the underlying causes of different types of alcohol-related pain, such as alcoholic neuropathy and allodynia, and how they develop at the spinal cord level. The researchers aimed to examine the role of microglia, immune cells in the central nervous system, in the development of chronic alcohol-induced allodynia and neuropathy.
Alcoholic neuropathy refers to nerve damage caused by long-term excessive alcohol consumption. It is a type of peripheral neuropathy that affects the peripheral nerves, which are responsible for transmitting signals between the brain, spinal cord, and the rest of the body.
Chronic alcohol use can lead to nutritional deficiencies and toxins that directly damage the nerves, resulting in symptoms such as pain, tingling, numbness, muscle weakness, and problems with coordination and balance. Alcoholic neuropathy typically affects the extremities, such as the hands and feet, and can have a significant impact on a person’s quality of life.
Allodynia, on the other hand, is a condition characterized by the perception of pain from normally non-painful stimuli. In other words, it is the experience of pain in response to a stimulus that would not typically be painful, such as a light touch or gentle pressure.
“More than half of patients suffering from alcohol-related disorders develop pain. Chronic pain is considered a key factor contributing to the maintenance of alcohol use disorder because people drink more to reduce it. For this reason, we are focusing on the molecular mechanism that highlight the correlation between pain and alcohol consumption,” said study authors Marisa Roberto and Vittoria Borgonetti of the Scripps Research Institute.
To conduct their study, the researchers used adult mice divided into three groups: alcohol-dependent mice (excessive drinkers), mice with limited access to alcohol (moderate drinkers), and mice that had never been given alcohol. They employed a chronic intermittent ethanol vapour paradigm to induce alcohol dependence in the mice. This paradigm involved cycles of alcohol exposure and withdrawal, mimicking the development of alcohol dependence in humans. The mice were then subjected to various tests to measure mechanical allodynia and neuropathic pain.
The researchers found that mice with alcohol dependence exhibited higher levels of mechanical allodynia compared to both moderate drinkers and alcohol-naïve mice. They also observed changes in protein levels in the spinal cord and sciatic nerve of alcohol-dependent mice, particularly in microglial cells. These changes suggested an activation of microglia and involvement of inflammatory processes in the development of alcohol-induced pain.
The researchers also found that there were two different types of pain conditions that occurred as a result of alcohol use. In mice that were dependent on alcohol, they experienced a condition called allodynia, which means they became more sensitive to pain during the period of alcohol withdrawal. However, when these dependent mice were given access to alcohol again, their pain sensitivity significantly decreased.
On the other hand, in mice that were not dependent on alcohol, about half of them also showed increased sensitivity to pain (hyperalgesia) during alcohol withdrawal. This is similar to what the dependent mice experienced. However, the key difference is that in these non-dependent mice, the increased pain sensitivity did not go away when they were exposed to alcohol again. The pain persisted even after re-exposure to alcohol.
“The study highlights two different conditions of alcohol consumption: excessive drinkers who develop alcohol dependence, and moderate drinkers, those who make daily recreational alcohol consumption. These two different conditions showed different types of pain: withdrawal hyperalgesia in excessive drinkers who develop dependence and alcohol neuropathy in 50 percent of moderate drinkers,” Roberto and Borgonetti told PsyPost.
“Hyperalgesia is a transient pain condition, closely related to alcohol withdrawal and is part of those negative emotional states, which usually induce the patient to take additional alcohol. Alcoholic neuropathy is a persistent and hardly reversible damage of the somatosensory system, which is associated with the consumption of alcohol in recreational amounts and is not related to addiction; therefore, it does not resolve with the intake of additional alcoholic beverages, which, on the contrary, accentuates it.”
Both of these pain conditions involved intense activation of microglia in the spinal cord tissue of the mice. Microglia are known to play a role in the body’s response to injury or inflammation.
Interestingly, the two pain conditions seemed to involve different pathways within the microglia. In the dependent mice with abstinence-related hypersensitivity, we noticed an increase in the expression of a protein called IL-6 and the activation of another protein called ERK44/42. However, these changes were not observed in the mice with alcohol-evoked neuropathic pain.
These findings contribute to a better understanding of the relationship between chronic pain and alcohol use disorder, highlighting the complex interactions between alcohol consumption, pain, and the immune system.
“It is important to understand the molecular mechanisms that highlight the two-way relationship between chronic pain and alcohol dependence,” Roberto and Borgonetti said. “In fact, the two forms of pain share strong inflammation, but what we have observed is that specific inflammatory molecules are increased only in conditions of withdrawal hyperalgesia and not in neuropathy. This suggests that these two forms of pain may be driven by different molecular mechanisms.”
The study, “Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: A mouse model of alcohol-evoked neuropathic pain“, was authored by Vittoria Borgonetti, Amanda J. Roberts, Michal Bajo, Nicoletta Galeotti, and Marisa Roberto.
