Philadelphia University + Thomas Jefferson University

Jefferson Researchers Identify New Target for Chronic Pain

Discovery of a phosphorylation event outside of the cell offers new avenue for targeting chronic and pathologic pain, a new study reports.

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Researchers have shown that the NMDA receptor on neurons plays a central role in pathologic pain, but it’s also important in many other neurological processes such as memory and learning, making it a poor target for direct drug inhibition.

In an elegant series of studies, Dr. Dalva and colleagues from New York University and the University of Texas at Dallas, showed that in response to pain, a second receptor, the ephrin B receptor, is phosphorylated outside of the neuron. This extracellular protein modification allows the ephrin B receptor, EphB2, to glom onto the NMDA receptor. This interaction then moves the NMDA receptors into the synaptic space, and modifies NMDA receptor function, resulting in increased pain sensitivity.

The researchers also showed that chemicals that block the interaction between the EphB2 and the NMDA receptor block pain. The converse was also true. By artificially promoting the interaction between these two receptors, neurons became oversensitive to pain, such that a mere touch would cause a painful reaction, or allodynia.

“Because the protein modification that initiates nerve sensitivity to pain occurs outside of the cell, it offers us an easier target for drug development,” says Dr. Dalva. “This is a promising advance in the field of pain management.”

The discovery that phosphorylation can drive NMDA receptors to synaptic sites provides neuroscientists a new tool with which to study synaptic development, learning and memory, and pain — all of which depend on the localization of NMDA receptors to synaptic sites.

The research was supported by National Institute on Drug Abuse (DA022727), National Institute of Mental Health (MH100093), National Institute of General Medicine (GM102575), National Center for Research Resources (RR027990), 100 Women in Hedge Fund Foundation, National Eye Institute Vision Training Grant (EY007035), National Institute of Neurological Disorders and Stroke (NS050276), National Institute of Neurological Disorders and Stroke (NS065926), and The Vicki and Jack Farber Foundation.

The authors have declared that no competing interests exist.

Article reference:  Kenji Hanamura, Halley R Washburn, Sean I Sheffler-Collins, Nan L Xia, Nathan Henderson, Dipti V Tillu, Shayne Hasler, Daniel S Spellman, Guoan Zhang, Thomas A Neubert, Theodore J Price, Matthew B Dalva. “Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain,” 2017 PLOS Biol 15(7): e2002457, DOI: 10.1371, 2017.

By Edyta Zielinkska