A tiny enzyme may hold the key to safer pain relief

The work was co-led by Matthew Dalva, director of the Tulane Brain Institute and professor of cell and molecular biology in the School of Science and Engineering, together with Ted Price at the University of Texas at Dallas. Their study shows that neurons can release an enzyme outside the cell that activates pain signals following an injury. The findings, reported in Science, also shed new light on how brain cells strengthen their connections during learning and memory.

External Enzyme Linked to Pain Activation

"This finding changes our fundamental understanding of how neurons communicate," Dalva said. "We've discovered that 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."

The researchers identified this enzyme as vertebrate lonesome kinase (VLK). They found that neurons use VLK to communicate in the space surrounding the cells, where it alters nearby proteins in ways that can influence how signals travel between nerve cells.

VLK's Role in Cell Signaling and Drug Development

"This is one of the first demonstrations that phosphorylation can control how cells interact in the extracellular space," Dalva said. "It opens up an entirely new way of thinking about how to influence cell behavior and potentially a simpler way to design drugs that act from the outside rather than having to penetrate the cell."

The team discovered that active neurons release VLK, which increases the activity of a receptor involved in pain, learning and memory. When researchers removed VLK from pain-sensing neurons in mice, the animals did not experience normal post-surgical pain, yet their movement and sensory abilities remained intact. When VLK levels were increased, pain responses intensified.

Implications for Pain, Learning and Neural Plasticity

"This study gets to the core of how synaptic plasticity works -- how connections between neurons evolve," said Price, director of the Center for Advanced Pain Studies, professor of neuroscience at the University of Texas at Dallas' School of Behavioral and Brain Sciences and a co-corresponding author of the study. "It has very broad implications for neuroscience, especially in understanding how pain and learning share similar molecular mechanisms."

Dalva noted that the results point toward a safer strategy for altering pain pathways by focusing on enzymes such as VLK instead of blocking NMDA receptors. NMDA receptors help regulate communication between neurons but can cause significant side effects when disrupted.

Pathway May Simplify Future Drug Design

The findings also offer one of the first examples of how to influence interactions between proteins on the cell surface without entering the cell itself. Dalva said this could make drug development easier and reduce unintended effects, since the therapeutic agent would work outside the cell.

Next steps include determining whether this mechanism affects only a small set of proteins or represents a wider biological process that has gone largely unnoticed. If it proves to be widespread, it may reshape treatment strategies for neurological and other diseases.

Large Collaborative Effort

The research was carried out in partnership with colleagues at The University of Texas Health Science Center at San Antonio, The University of Texas MD Anderson Cancer Center, the University of Houston, Princeton University, the University of Wisconsin-Madison, New York University Grossman School of Medicine and Thomas Jefferson University.

"Our findings were only possible through this kind of collaboration," Dalva said. "By combining Tulane's expertise in synaptic biology with the strengths of our partners, we were able to reveal a mechanism that has implications not just for pain, but for learning and memory across species."

The project was supported by grants from the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse and the National Center for Research Resources, all part of the National Institutes of Health. Co-first authors include Dr. Sravya Kolluru, Dr. Praveen Chander and Dr. Kristina Washburn, all members of The Dalva Lab at Tulane.