Pain researchers have been studying the wrong part of the nerve cell. Pain-sensing neurons have specialised endings in the skin and organs where injury actually happens, but most experiments use other parts of the neuron—sometimes a metre away from the site of damage. This matters because the nerve ending is where inflammatory mediators released during tissue damage activate pain receptors, triggering calcium signals that sustain pain and aid healing. Those calcium signals rely on internal stores that must be refilled, a process controlled by two proteins, STIM1 and Orai1, which work together to bring calcium back into the cell. Disrupting this protein complex reduces pain signals in animal models of chronic pain, but no one has studied whether the same refilling mechanism operates in the nerve endings themselves. This fellowship will map where calcium stores and STIM1/Orai1 are located in the endings, confirm that active refilling occurs there, and investigate a scaffolding protein called Extended Synaptotagmin-1 that may enable the STIM1-Orai1 interaction. This is fundamental science—it will not produce a new painkiller tomorrow. But understanding how nerve endings actually manage calcium during inflammation could eventually guide the development of therapies that target pain at its source, rather than at distant parts of the neuron.
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Is pain research being done in the wrong place? Pain-sensing neurons have tiny endings/fibres in the skin and organs to allow the body to sense painful stimuli. On a molecular level, it is the presence of different proteins (receptors) in these endings that allow harmful events to be converted into electrical signals enabling us to ultimately feel pain. However, rather than using pain-sensing neuron endings to understand how pain signalling occurs, other areas of these neurons are routinely used instead. There are obvious issues with this as there are differences in size, shape and location of the different parts of the pain-sensing neuron. For example, in humans, there can be approximately one metre between where injury occurs at the skin of the finger to the spine, where the other parts of the neuron are located. Therefore, does it make sense to use these other areas as an accurate representation of what happens at the site of injury? These issues must be addressed and ideally, pain-sensing nerve endings need to be used to study pain. If this can be established, it would revolutionise how pain research is done. When tissue damage occurs, so-called ‘inflammatory mediators’ are released from the site of injury and activate the receptors at the nerve endings, ultimately leading to a heightened sense of pain sensation with the associated redness and swelling. This ‘inflammatory’ response is important for effective healing to occur therefore, it is crucial to understand inflammatory pain signalling (IPS) from a molecular point of view. Ca2+ signalling is well understood as part of the IPS process; it is important for producing increased pain signals to be maintained and aid the healing process. Delving deeper into IPS, neurons have vital Ca2+ stores that release Ca2+ after pain receptor activation. It is evident that inflammatory nerve responses rely heavily on these Ca2+ stores, therefore, just as a car would need to be refueled to continue to drive, the replenishment of Ca2+ stores is critical for efficient and sustained Ca2+ release during inflammation or injury. Two proteins, STIM1 and Orai1, are known to perform refilling of Ca2+ stores. When Ca2+ is released from these stores, the reduction in Ca2+ levels leads to STIM1 and Orai1 physically interacting. The subsequent complex formed allows Ca2+ entry into the cell from the outside environment. This Ca2+ is then taken up into the stores and refilling is completed. STIM1 and Orai1 are known to be involved with IPS; by disrupting this complex, pain signals can be reduced. Additionally, activity of these proteins is increased in animal models of chronic pain, thereby suggesting a role in these types of conditions. However, this process is not understood in the pain-sensing nerve endings. Therefore, as part of this fellowship I will investigate the following objectives: Identifying Ca2+ stores in the nerve endings and understanding where STIM1/Orai1 are found relative to these stores Show that active Ca2+ refilling in the nerve ending occurs Investigating a scaffolding protein (Extended Synaptotagmin-1), known to allow STIM1-Orai1 interaction, in the nerve endings. Taken together, this fellowship will allow me to understand how refilling in the nerve endings occurs; such fundamental understanding will underpin future translational research to provide new therapeutic and avenues to treat inflammatory pain conditions and provide me with a foundation to further my independent career.
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