"The hunt is on for non-addictive pain treatments – our research could help"

Chronic pain is the largest contributor to diminished life experience on the planet. It is pain that lasts over three months, and it can limit a person physically, emotionally and lead to social isolation.

A major issue with modern healthcare systems is that current drug therapies are still relatively ineffective. They are also associated with problematic side effects, such as the addictive potential of opioids.

After an operation, many people are treated for pain with opioid-based drugs, and a proportion cannot then wean themselves off. Overusing opioids can lead to other health problems, such as breathing difficulties, and an overdose can cause death.

More than 16 million people worldwide are affected by opioid use disorder, and over 2.1 million are based in the US.

That’s why the hunt is on for non-opioid-based treatments for pain – and our research published in Nature could help find a solution.

It’s been known for several decades now that there are proteins called ‘transporters’ that move molecules across the cell membranes in our bodies. My research explores how transporters recognise and move drug molecules, and how they operate across organs like the brain, intestines, liver and kidneys.

The biggest challenge is understanding how these transporters work. This would enable clinical use and drive the development of new drugs and treatments.

Our research on chronic pain all started when Professor David Bennett from the Nuffield Department of Clinical Neuroscience reached out to me. His team carried out a questionnaire using the UK Biobank, a large biomedical database, investigating the underlying genetics predisposing people to chronic pain.

They had identified a genetic variation in a transporter that they knew was associated with chronic pain, but they didn’t know its function.

We ran tests to understand the transporter’s structure and found connections with a molecule called spermidine, which research shows can influence neuronal excitability. In collaboration with David’s team, we also discovered that the transporter could be found in a region of the nervous system called the dorsal root ganglion (DRG). DRG neurons convey sensory inputs like touch, pain or temperature from tissues such as skin. This information is transmitted to the spinal cord and then to the brain.

David’s team next found that the transporter was linked to pain in a mouse study. In particular, we found that after removing the transporter from nociceptors, which are specialised DRG neurons that detect pain, mice were less sensitive to high temperatures and pain-inducing chemicals.

Together, our teams, along with colleagues in the USA, UK, Norway, Sweden and at AstraZeneca, were able to connect pain to a molecular mechanism. That means there’s a potential opportunity to create a drug that treats it. Unlike opioids, which activate nerve cells in the brain and can alter multiple neural circuits resulting in side effects such as addiction, it would target nociceptors specifically. If it can treat chronic pain, it could provide a way of helping people off opioids.

Our work wouldn’t have been possible without the fundamental research to connect people’s behaviour and experience to how molecules and cells work. When we started this research project, we didn’t know we would target chronic pain, but we could move resources quickly to tackle it when the opportunity presented itself as part of our ongoing research.

This freedom to operate is what attracted me to the Wellcome Discovery Awards. It allows you to work on broad research questions, connecting different areas of biology and medicine.

I think the longevity of funding is fundamental to supporting bold research. Long-term funding gives you and your team the confidence to take risks, and this is often when the most important discoveries are made.

We are now doing further research on the ‘pain transporter’ and exploring the potential for developing new medications to treat pain with reduced side effects. For example, doctors could now take this research and start making connections to improve their understanding of pain. It's all very exciting and could result in a lot more discoveries.