A newly discovered ‘pain switch’ in our brains could unlock safer drugs

In a major breakthrough in brain science, researchers and collaborators from New Orleans have discovered a nerve signaling mechanism that occurs outside the cell and switches on a “pain switch.” This marks a significant overhaul in the way we understand how pain receptors in the brain work, and it could shed light on a path to safer pain medications that can effectively provide relief without the usual side effects.

The scientists recognized that phosphorylation – a key process by which proteins are regulated – was well understood when it occurred inside a cell, but its function outside the cell was less clear. They wanted to know whether this change, which occurs on the outside of many synaptic proteins, actually changes the way nerve connections (synapses) signal or influence a living animal’s behavior.

They discovered that nerve cells communicate outside the cell with an enzyme called vertebrate solitary kinase (VLK); this enzyme changes proteins in the space between neurons. When active neurons release VLK, it enhances the function of a pain receptor. This finding “opens up a whole new way of thinking about how to influence cell behavior and potentially an easier way to design drugs that work from the outside rather than entering the cell,” said Matthew Dalva, a brain scientist at Tulane University who led the research into this mechanism. appeared in the news Science last week.

When the team removed VLK from pain-sensing neurons in mice, the animals did not feel the usual pain that follows surgery, but continued to experience sensations from their environment as normal; increasing the level of VLK in those neurons increased pain responses.

In other words, “an enzyme released by neurons can modify proteins on the outside of other cells to turn on pain signaling — without affecting normal movement or sensation,” Dalva explained.

This is important because it gives us a new way to think about developing drugs to treat pain by affecting cells from outside rather than entering the cell. By targeting enzymes like VLK instead of blocking receptors at synapses (which can lead to side effects), we may be able to provide pain relief more easily.

Obviously, much more work will be needed to explore the implications of this finding before we see the next generation of painkillers based on it. The researchers plan to follow up on this work by determining how broadly this affects proteins involved in neurological functioning, and what that could mean for the treatment of brain diseases other than pain.

Source: Tulane University