Chronic pain research breakthrough identifies promising drug target

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.

With findings published in Nature, 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. The research, led by the University of Oxford and supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre (OH BRC), offers a promising, new, specific target against which to develop a drug to alleviate chronic pain.

The mystery of 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, associated health impacts.

Professor David Bennett, Head of the Division of Clinical Neurology and Professor of Neurology and Neurobiology at the University of Oxford, and OH BRC Pain Co-Theme Lead, said: “Chronic pain remains a huge societal problem as it is becoming more common and current treatments fail. We need to understand the mechanisms behind chronic pain in humans and importantly identify new analgesic drug targets. This project has been an exciting scientific journey, showcasing the power of collaboration across diverse medical disciplines.

“We discovered a new pain gene, gained insights into the atomic structure of this molecule, and connected its function to the excitability of neurons that respond to tissue injury. Ultimately, our findings reveal a promising new target for the treatment of chronic pain.”

Discovering a pain-related gene

To understand why some people are more affected by chronic pain, the research team led by Professor David Bennett at the University of Oxford, 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 and 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.

Professor Simon Newstead, David Phillips Chair of Molecular Biophysics in the Department of Biochemistry and Kavli Institute for NanoScience Discovery at the University of Oxford, said: “Significant discoveries occur when we grasp how the complex tissues and organs in our bodies function and communicate. Membrane transporters play a fundamental role in this communication.

“Our findings now reveal a new link between membrane transport and chronic pain, paving the way for a deeper understanding of how metabolism and pain are connected in the human body.”

Hope on the horizon?

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.

Michael Dunn, Director of Discovery Research at Wellcome, said: “This is remarkable research, across all the scales of life from our genetics, to atomic structures, to cellular mechanisms.

“Finding the first definitive link in human bodies to the cause behind chronic pain is profoundly important. It demonstrates the importance of long-term, tenacious, discovery science. Now, scientists can focus on a promising target to treat chronic pain, potentially improving the health of millions around the world.”