Silencing musculoskeletal pain: can we target spontaneously active neurons?

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.

Musculoskeletal pain conditions are a leading cause of disability and are poorly treated by existing analgesic medications. We know that pain in these conditions can be effectively treated by blocking sensory afferent input in the periphery. This is evidenced, for example, by the acute analgesic effects of local anaesthetic block or by the attenuation of pain following joint replacements in osteoarthritis. However, a non-selective block of all afferent fibres (e.g. via perineural local anaesthetic application) is not viable due to safety concerns. Thus, our proposal will focus on determining which peripheral afferents become sensitised in musculoskeletal pain to facilitate the development of more targeted analgesic treatments. We will focus on spontaneous sensory neuron activity because this has been recorded from nociceptors of individuals living with chronic musculoskeletal pain, as well as in animal models.

Our proposal will use cutting-edge optical imaging technologies, which allow the study of spontaneous firing in afferents in models of musculoskeletal pain. We will identify which types of sensory neurons become spontaneously active using a combination of functional, anatomical and genetic strategies. Once we have identified the major subpopulation of neurons where spontaneous activity resides, we will use a chemogenetic strategy to silence this population and will assess impact on pain behaviours. To understand the relationship between spontaneous activity and rodent behaviour in musculoskeletal pain, we will optimise the use of Miniscopes, so that we can record activity from DRG neurons in freely behaving awake animals.

Our proposal will reveal which sensory neuron class we should target in order to eliminate spontaneous activity and consequent pain behaviours. This will help refine any analgesic drug development strategies that are currently being developed for the treatment of musculoskeletal pain.