A Newly Discovered “Pain Switch” in the Brain Could Lead to Safer Pain Medications
In a major breakthrough, scientists have identified a previously unknown “pain switch” in the brain — a discovery that could reshape the future of pain medications. The key lies in an enzyme called vertebrate lonesome kinase (VLK), which neurons release into the space outside the cell, triggering pain signaling in response to injury.
How the Pain Switch Works
Traditionally, our understanding of pain signaling centers on processes within the cell. But the Tulane University-led research team found that neurons communicate in a different—and surprising—way: by secreting VLK into the extracellular space. Once there, VLK modifies proteins in neighboring nerve cells, effectively turning up pain signaling.
Their experiments in mice demonstrated the power of VLK. When VLK was removed from pain-sensing neurons, the animals experienced much less post-surgery pain — yet they retained normal sensory function and movement. Conversely, increasing VLK levels intensified pain responses.
Why This Matters for Safer Pain Treatments
Targeting VLK offers a promising alternative to traditional pain therapies — many of which act on intracellular mechanisms or critical receptors like NMDA, and can come with serious side effects.
Because VLK functions outside the cell, drugs designed to regulate it could work from the extracellular space, potentially avoiding the need to penetrate the cell. This could simplify drug design and also minimize off-target effects.
Moreover, the discovery sheds new light on how phosphorylation (a key mechanism in protein regulation) can influence interactions between cell-surface proteins — not just inside cells but between them.
Broader Implications and Next Steps
Beyond pain, this mechanism may have deeper implications for understanding how neurons adapt and form connections. The same VLK-mediated process could play a role in learning and memory, hinting at a broader biological function.
The research team is now investigating how widespread this extracellular signaling mechanism is. Is VLK acting on just a few proteins, or is this a more general phenomenon? The answer could open doors to treatments not only for pain but also for other neurological conditions.
This discovery comes from a partnership of researchers at Tulane University and eight other institutions, including the University of Texas at Dallas, the University of Wisconsin–Madison, Princeton University, and more. The study was supported by grants from the National Institutes of Health, notably from the National Institute of Neurological Disorders and Stroke.
