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Optochemical control of P2X receptor ion channels: dissecting their role in pain signalling

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Remote control for pain studies

Chronic pain affects billions of people globally, and the associated socioeconomic costs amount to around EUR 300 billion annually in Europe alone. The underlying mechanisms of chronic pain are still poorly understood and treatments are thus mostly ineffective.

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Scientific advancements have made it possible to manipulate molecules and cells with light. By taking advantage of the high spatial and temporal precision of light it is possible to address many important biological questions. EU-funded researchers of the project P2X IN PAIN (Optochemical control of P2X receptor ion channels: Dissecting their role in pain signalling) developed and employed optochemical and optogenetic tools to study pain signalling. They focused on P2X receptors as they have been linked to chronic pain and are expressed in nociceptors, which act as specialised peripheral pain sensors. Researchers engineered mammalian P2X receptor ion channels to enable reversible manipulation via light for optical control. Blue light is used to open these ligand-gated ion channels and ultraviolet light returns it to its original state. This non-invasive method provided excellent spatiotemporal precision for receptor activation in P2X2 and P2X3 receptor ion channels. The algae light-activated ion channel called channelrhodopsin (ChR2) was also used for the research. A breakthrough, the team generated a light-gated P2X3 receptor knock-in mouse line using CRISPR/Cas9 for genome editing. This mouse model will enable the in vivo study of the P2X3 receptor in health and disease through the manipulation of this specific protein. Scientists studied nociceptor activation and behavioural response in freely behaving mice at the millisecond timescale. ChR2 effectively controlled nociceptor signalling in the skin and provided novel insights into the organisation of protective behavioural responses. The P2X IN PAIN study has successfully provided proof-of-concept for the utility of optogenetics in remotely controlling peripheral nociceptive pathways at unparalleled spatiotemporal resolution. The results are soon to be published in peer-reviewed papers. These tools and study findings should prove invaluable in developing and testing targeted drugs for chronic pain management.


Chronic pain, P2X IN PAIN, optochemical, P2X receptor, nociceptors

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