A new paper published in Nature shows how, in a collaborative project across diverse medical disciplines, Oxford researchers from the Nuffield Department of Clinical Neurosciences (NDCN) and the Department of Biochemistry have identified a new genetic link to pain.
Chronic pain is life-changing and considered one of the leading causes of disability worldwide, making daily life difficult for millions of people around the world, and exacerbating personal and economic burdens. Despite established theories about the molecular mechanisms behind it, scientists have been unable to identify the specific processes in the body responsible, until now.
In an exciting collaboration, a team led by NDCN's Professor David Bennett , and Professor Simon Newstead in the Department of Biochemistry and Kavli Institute for NanoScience Discovery, have 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 findings of the research, funded by Wellcome and supported by the NIHR Oxford Health Biomedical Research Centre (OH BRC), offers a promising, new, specific target against which to develop a drug to alleviate chronic pain.
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.
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, 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.'
To understand why some people are more affected by chronic pain, the research team in NDCN first 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. Lead author on the paper, senior post-doctoral researcher, Dr Steven Middleton explained: 'Linking SLC45A4 to chronic pain in humans was really exciting, but the next challenge was unravelling exactly what SLC45A4 does in the body. Remarkably, we identified that SLC45A4 is the long-awaited neuronal polyamine transporter, which is particularly important in regulating how some nerves respond to painful stimuli. This has broadened our understanding of pain signalling in the body and opened new avenues of research directed at treating chronic pain. Our work exemplifies the power of discovery science and multi-disciplinary collaboration.'
Collaborating with Professor Simon Newstead in the Department of Biochemistry 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 also discovered that this gene was present at high levels in the dorsal root ganglion, the region where sensory neurons 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. 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 into the SLC45A4 gene.
Professor Simon Newstead 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.'
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.
Professor Bennett concluded: '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.'
The full paper ' SLC45A4 is a pain gene encoding a neuronal polyamine transporter ' is published in Nature .
