A new study led by researchers at the University of Oxford has identified a genetic link to chronic pain, opening up potential for new treatments. The research team, led by Professor David Bennett from the Nuffield Department of Clinical Neurosciences (NDCN) and Professor Simon Newstead in the Department of Biochemistry and Kavli Institute for NanoScience Discovery, focused on understanding why some people are more affected by chronic pain.
Chronic pain is recognized as a major cause of disability globally and significantly impacts daily life and economic productivity. While previous theories suggested that polyamines—chemicals produced naturally in the body—might play a role in nerve cell overactivity linked to pain, specific mechanisms remained unclear.
Professor Bennett stated: "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."
The researchers used data from UK Biobank to compare genetics with self-reported pain levels. They found that individuals with a variant of the SLC45A4 gene were more likely to experience higher levels of pain. These results were confirmed using additional data from large population studies such as FinnGen.
Dr Steven Middleton, senior post-doctoral researcher and lead author on the paper, 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."
The structure of this molecular transporter was determined using cryo-electron microscopy—a first for this protein—by collaborating with Professor Newstead's group. The transporter moves polyamines across nerve cells, supporting its role in modulating nerve response to injury.
Further investigation showed that SLC45A4 is present at high levels in sensory neurons within the dorsal root ganglion, an area involved in transmitting information about touch and pain from skin and muscle to the brain. In experiments with mice lacking this gene, researchers observed reduced responses to typical pain stimuli. Although mouse nervous systems differ from those of humans, shared basic mechanisms suggest promise for further research into this target.
Professor 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."
Current treatment options often rely on opioids that affect multiple pathways within the brain but can result in addiction or other health problems. The identification of SLC45A4 as a target could allow development of drugs that address chronic pain more specifically.
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 study was funded by Wellcome Trust with support from NIHR Oxford Health Biomedical Research Centre (OH BRC). Full details are published under ‘SLC45A4 is a pain gene encoding a neuronal polyamine transporter' in Nature.