Silencing musculoskeletal pain: can we target spontaneously active neurons?

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Chronic pain in joints and muscles is one of the leading causes of disability worldwide. The pain killers we have do not work for many people and often have terrible side effects, like addiction in the case of opioids. We therefore urgently need to increase our understanding of what causes chronic muscle and joint pain, to help us develop better treatments. One particularly promising idea could be to target the nerves that carry sensory information from our body (e.g. touch of the skin) to the spinal cord and brain. The sensory nerve fibres that transmit painful information are meant to be silent unless we injure ourselves. However, in conditions, like osteo- and rheumatoid arthritis, they are known to spontaneously emit signals. This is thought to be an important cause of chronic pain. Indeed, it is believed to be a likely reason for flare-ups and spontaneous pain attacks, which are extremely disruptive to individuals living with arthritis. Despite this, we understand very little about how these spontaneous signals arise. Most importantly, we do not actually know which type of peripheral nerve fibres (there are many different types) are primarily responsible. Without this information, we cannot develop specific treatments that are aimed just at the malfunctioning nerve fibres. Our proposal aims to change this. We are working with a recently developed imaging technique that allows us to record spontaneous signals in hundreds of nerve fibres at the same time, rather than having to sample them one-by-one - as was necessary previously. With this technique and other recently developed tools, we can determine exactly which types of nerve fibres develop spontaneous signals in animal models of arthritis. We will then use chemical tools to specifically silence the spontaneous nerve fibres and assess whether this reduces pain in our models. At the end of our work, we will have fully characterised the peripheral nerve fibres which are responsible for spontaneous pain. We will share this information with drug companies to help their efforts to develop the improved pain killers that millions of individuals so desperately need.