Changes to the nervous system during chronic pain remain poorly understood. What we do know is that nerve cells in the spinal cord play an important role in pain signalling because the spinal cord is the first site where information from our bodies is processed to ultimately shape sensory experience. Despite this, our knowledge of the specific nerve cell populations within spinal pain signalling circuits is limited. This poses a major barrier to new and more effective pain therapies.
Our group has developed a range of techniques to study pain signalling at the level of individual nerve cells, circuits, and in the whole model, all built around a new technology termed ‘optogenetics’. Optogenetics is a powerful tool that uses light-sensitive proteins to switch nerve cell activity on or off. This gives us the capacity to study the function of brain and spinal cord circuits with unprecedented detail. Importantly, we are currently leading efforts to bring this technology to bear in spinal pain signalling research. We are therefore well positioned to make a substantial contribution to our understanding of pain signalling circuits.
Using these optogenetic approaches, we have collected pilot data on three different types of spinal nerve cells that can be identified by proteins specific to each:
- calretinin (CR)
- parvalbumin (PV)
- choline acetyltransferase (ChAT)
Furthermore, our initial results suggest that each cell type is important for different aspects of the pain experience. For example, the CR cells are predominantly excitatory and make extensive connections with each other. This leads us to believe they act as a potential ‘pain amplifier’ population. PV cells are inhibitory and make a unique kind of connection that suggests they are important for ensuring that sensations of touch do not cause pain. By extension, if PV cell function is compromised this could cause a symptom called allodynia where touch becomes painful. Finally, ChAT cells are inhibitory and arranged along the spinal cord in a way that suggests they are important for limiting the spread of pain signals. A loss of this ChAT cell signalling would result in more widespread pain signalling and may result in radiating pain (ie. spreading of painful areas).
The current project aims to test these predictions using our optogenetic preparations and two models of chronic pain. Importantly, one of the models reflects inflammatory pain (eg, arthritis), whereas the other model reflects neuropathic pain (eg, nerve injury). This will allow us to assess the relevance of each cell type (CR, PV, and ChAT) to the two main forms of chronic pain.
The results of this work will advance our understanding of how pain signals are relayed through the spinal cord under normal conditions and in chronic pain states. This information can then be used to develop new pain drugs that specifically modify CR, PV, and ChAT cell activity and restore spinal pain signalling circuits to normal.
A/Prof Brett Graham, Dr Phil Jobling, Ms Kelly Smith