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For the first time, a team of researchers have identified a new genetic link to pain, offering a promising drug target to alleviate chronic pain.

Chronic pain is life-changing and considered one of the leading causes of disability worldwide. Despite established theories about the molecular mechanisms behind it, scientists have been unable to identify the specific processes in the body responsible, until now.

Researchers funded by Wellcome have, for the first time, identified a new genetic link to pain, determined the structure of the molecular transporter that this gene encodes and linked its function to pain. Led by Oxford, in collaboration with the Nuffield Department of Medicine’s Target Discovery Institute and supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre (OH BRC), the findings offer a promising, new, specific target to develop a drug for alleviating chronic pain.

Chronic pain underlines many long-term health conditions, making daily life difficult for millions of people around the world and exacerbating personal and economic burdens. Determining the root cause behind how pain signals are detected and regulated in the nervous system has long challenged scientists.

In many chronic pain conditions, nociceptors – nerve cells that detect tissue injury – become overactive and send too many pain signals to the brain, causing more distress than usual. The regulation of these signals is not fully understood, although some studies have linked these changes to polyamines – natural chemicals produced by the body to help cells carry out a variety of normal functions. For example, people with conditions such as arthritis often have a higher concentration of polyamines.

Over time, a higher concentration of polyamines is thought to contribute to over-sensitising nerve cells causing long-term damage and ultimately leading to chronic pain by sending more pain signals to the brain than usual. This means that even low-level stimuli might feel more painful than normal.

However, until now, these theories have been unproven. Without a known, specific target, chronic pain is hard to treat and has led to a reliance on blunt force - powerful opioids. While effective at reducing pain, these drugs act in multiple brain pathways and can result in addiction, leading to profound, long-term health impacts.

To understand why some people are more affected by chronic pain, the research team led by Professor David Bennett in the Nuffield Department of Clinical Neurosciences used UK Biobank to compare genetic data with participant responses to a questionnaire on pain. They found that people with a variant of a gene called SLC45A4 were more likely to report higher levels of pain. These findings were replicated when using data from other major population studies, such as FinnGen.

The researchers then set out to understand what this gene encodes. They were able to show that SLC45A4 codes for a molecular transporter responsible for moving polyamines – such as spermidine – across nerve cells. Collaborating with Professor Simon Newstead, Department of Biochemistry and Kavli Institute for NanoScience Discovery, using cryo-electron microscopy, the team determined the structure of the transporter in humans, the first time this has been done in 3D, confirming it is responsible for sending polyamines across nerve cells.

The research team then discovered that this gene was present at high levels in the dorsal root ganglion, the region where sensory neurons which carry information from skin and muscle. Nerve cells in this region are responsible for detecting pain, with the number of signals sent to the brain responsible for modulating our pain response.

Conducting experiments in mice lacking SLC45A4 – a gene they share with humans – the animals showed a lower response to typical pain stimuli. Neurons that detect tissue injury, called 'polymodal nociceptors,' were less responsive to heat and mechanical stimuli. The mouse nervous system is not identical to humans, but there are plenty of basic mechanisms shared between them, humans and other mammals, showing promise for future research.

When the research team began to investigate the genetic determinants of chronic pain, they did not anticipate finding real-world applications. Now, researchers can begin to study the SLC45A4 gene in more detail. For example, researchers could use existing datasets to understand how other factors, such as diet, influence the transporter. They will be able to use the detailed structural knowledge of this transporter to understand how genetic variations impact on function and potentially design novel therapeutics by targeting critical regions of the transporter.

Clinicians can now also begin to use this research to build a new understanding of pain management. With further research, if a successful drug can be developed, it could reduce long-term, chronic pain without relying on strong opioids, leading to safer and more effective treatments for patients worldwide.

To read the full study, visit the Nature website: https://www.nature.com/articles/s41586-025-09326-y