Chronic nerve pain is a difficult thing to treat. “It’s a complex sensory and emotional experience associated with actual or potential tissue damage,” said Jing-Dun Xie, professor in the of Department of Anesthesiology at Sun Yat-sen University Cancer Center, China.

While treatment options exist, they offer limited relief and can produce severe side effects, rarely providing a treatment for the root cause. Xie suspects that our finite tool belt against chronic pain may be attributed to our sub-optimal understanding of how the body regulates pain-related molecules.

In a recent study published in Advanced Science, Xie and his colleagues point to the potential role that a phenomenon called post-transcriptional RNA modification plays in coordinating functions related to pain by regulating certain proteins.

The role of the epitranscriptome

Neuropathic — or nerve — pain typically occurs as a result of damage to the nerves of the peripheral or central nervous system. “It is often described as a burning, shooting, or electric shock-like sensation, and can be accompanied by numbness or tingling,” said Xie. “It can be caused by various conditions, such as nerve injuries, diabetes, viral infections, or certain autoimmune diseases.”

Affecting 7-10% of the global population, it is a debilitating condition that significantly lowers quality of life, affecting not just the body, “but emotions, relationships, and the mind”. With a large number of affected people and limited therapeutic solutions, Xie and his team decided to take a look under the hood, targeting the epitranscriptome — a set of chemical modifications that can occur in RNA molecules — to provide answers.

“We know that acquired factors such as nerve injury often influence the expression […] proteins associated with neuropathic pain through epigenetic modifications, rather than altering the genetic coding sequence,” explained Qiang Liu a professor at the University of Science and Technology of China who was not involved in the study. “Epigenetic regulation is a reversible process, which suggests that pathological pain states can potentially be corrected by modulating epigenetic modifications.”

These modifications are like additional tags or edits made to RNA after it has been transcribed from DNA. Just as changes to any text can alter its meaning, modifications to RNA can affect how it functions, influencing various biological processes, including protein synthesis and the regulation of genes.

“When we came across literature reporting [a highly conserved RNA modification involved a variety of biological processes] can occur on mRNA and impact its stability and translation efficiency,” said Xie. “We immediately wondered whether [it] might also be involved in the progression of neuropathic pain.”

This specific modification, called N4-acetylcytidine or ac4C, is crucial for controlling RNA stability, where it goes in the cell, and how it influences the production of various proteins. As a result, Xie and his colleagues suspected that these changes might cause shifts in how pain is experienced.

A link between ac4C and chronic pain

Recent studies found a biomolecule called N-acetyltransferase 10 (NAT10) as the only known protein that controls ac4C-related changes. “However, it is still unknown whether ac4C is involved in neurological diseases, especially pain, which has always been our concern,” said Xin. “If ac4C is found to play a role in neuropathic pain, it may serve as a potential biomarker or therapeutic target for the development of more effective treatment strategies.”

To investigate, they identified which molecules were present in higher amounts in an area of the spine known to be critical for pain regulation in rats. They discovered that ac4C levels were elevated along with a protein called Vegfa following injury, suggesting that the ac4C modifications resulted in an upsurge in the production of this protein within neurons.

“Conversely, using RNA interference technology or chemical inhibitors to lower expression, [we] could effectively alleviate ‘neuron excitability’ and pain hypersensitivity caused by nerve injury in rats,” said the first author of the study, Ting Xu.

This is the first time this connection has been made, and while significant, Lui emphasizes that the research is still at an exploratory stage. Alongside identifying potential drug candidates suitable for human studies, he says, the team must grapple with the intricacies of formulation and delivery. Liu underscored the particular difficulty in developing drug delivery methods capable of penetrating the blood-brain barrier to target central nervous system molecules like NAT10.

Xie acknowledges this formidable challenge, stating, “There is still a significant gap to overcome in translating these mechanisms into viable biological targets for clinical applications.

“The timeline for the development of a commercial medication […] can vary widely and is difficult to accurately predict as it typically involves several stages of rigorous scientific investigation and regulatory processes, such as extensive pre-clinical studies, active clinical trials, and approvals from regulatory authorities, all of which can take several years.”

But the team is optimistic that even in providing these results, they are taking a huge leap forward, aiming to help doctors and patients in understanding how nerve pain occurs to come up with better solutions for those affected.

“A large number of patients and some doctors have insufficient understanding of neuropathic pain, often ignoring it as a co-morbid symptom of the disease,” Xie said. “By taking a serious approach to pain as a disease and delving deep into its underlying mechanisms, medical professionals can gain a better understanding of the cause, development, and prognosis of the disease, while also providing potential targets for treatment.

“By popularizing knowledge about the disease, patients can gain a better understanding of their condition, communicate more effectively with their doctors, and optimize the treatment process for their disease.”

Reference: Dan Xie, Wen-Jun Xin, Jing-Dun Xie, et al., Ac4C Enhances the Translation Efficiency of Vegfa mRNA and Mediates Central Sensitization in Spinal Dorsal Horn in Neuropathic Pain, Advanced Science (2023). DOI: 10.1002/advs.202303113

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