Chronic pain treatment

Proteins must function properly in the cell at the right time in the right place. Because of its complex dendritic structure and its function, this is more important in neurons than in other cells. Researchers at Thomas Jefferson University have now discovered that phosphorylation is a common type of protein modification that works in a novel way that alters the location of proteins that are critical to neuronal function and pathological pain. They found that phosphorylation could occur outside neurons and affect protein function, localization and pain.

Published on July 18 in PLOS Biology, the study provided a potential new goal of developing alternatives to existing painkilling medications.

The corresponding author, Dr Matthew Dalva, said that although we have not yet discovered the exact mechanism that led to such a modification, this finding offers the goal of developing new therapies and a powerful new tool for learning synapses in general.

Unlike pain caused by the effects of inflammation, the pathological pain usually comes from neuronal dysfunction, pain can be felt even without underlying cause or continue to be painful after a long period of time from the start of the event, such as migraine or chronic pain.

Researchers have shown that NMDA receptors in neurons play an important role in pathological pain but are also important in many other neurological processes such as memory and learning, making them an undesirable target of direct drug suppression.

In a series of studies, by Hospitalkhoj and the University of Texas at Dallas showed that the second receptor, ephrin B, is phosphorylated outside of neurons in response to pain. This extracellular protein modification allows the ephrin B receptor EphB2 to adhere to the NMDA receptor. This interaction then moves NMDA receptors into synaptic spaces and alters NMDA receptor function, resulting in increased pain sensitivity.

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The researchers also showed that chemicals that block the pain by blocking the interaction between EphB2 and NMDA receptors. The opposite is true. By artificially promoting the interaction between these two receptors, the neurons become hypersensitive to the pain so that touching alone can cause painful reactions or allodynia.

Dr. Dalva said: "It offers us an easier goal of drug development because protein modifications that cause neurological sensitivity to pain occur extracellularly." This is a promising step forward in pain management.