Pain has a large socio-economic impact, it is estimated that up to one in five Europeans (19%) suffers from chronic pain, costing the EU around €300 billion per annum. Understanding the molecular and cellular mechanisms underlying pain signalling is critical for the development of novel treatments. P2X receptors are ligand-gated ion channels opened by extracellular ATP. They have well-established roles in chronic pain, particularly in the case of P2X3, P2X4 and P2X7 subunits. However, a lack of sufficiently powerful tools has seriously handicapped our understanding of P2X receptors in these roles. Recent technological advances have now made it possible to engineer ligand-gated ion channels to be selectively controlled by light. This enables non-invasive control of native channel activity with high temporal and spatial resolution. Here it is proposed that a light-activated P2X4 receptor (LiP2X4R) will be engineered and used in vivo to dissect its precise role in pain signalling. In mice expressing LiP2X4R in neurons and microglia, LiP2X4 will be activated and any resultant pain-related behaviours monitored (e.g. mechanical and thermal pain hypersensitivity). This optogenetic approach will address important aspects of pain signalling mechanisms, including: the neuron-glia interactions that underlie pain signalling; and the specific contribution of P2X receptors towards pain signalling in vivo. It will enable the precise role of P2X receptors to be defined in a manner not possible before, and will provide insights to the mechanisms that underlie chronic pain processes.
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