Our nation is facing unprecedented challenges because of chronic pain. As pain relievers were made to be more and more powerful, there were unforeseen consequences from medicating so many people with really strong opiates. That is only one reason researchers have long been searching for alternative ways to treat pain, a search that’s becoming a more pressing issue. New work published in PLOS Biology presents a potential new target for the treatment of pain - phosphorylation outside of the cell.
As chemicals send signals in our body to carry out cellular function, one way messages are sent is through small modifications to proteins. One such modification is phosphorylation, in which an enzyme adds a phosphate group to an amino acid residue of a molecule. That alteration can change the shape of the protein, move the protein to another location, allow it to recruit other proteins, and carry out cell processes.
Phosphorylation is related to neuronal activity and pathological pain. There are several types of pain, like that from a burn or that from an impact. Pathological pain is different from other kinds of pain because it results from a dysfunction in neurons. It results in sensations of pain even when no hurtful stimulus is occurring, or a painful state that is maintained long after a painful event.
"Although we have yet to discover the exact mechanism that causes this modification, this finding offers both a target for developing new treatments and a strong new tool for studying synapses in general,” noted Matthew Dalva. He is Professor and Vice Chair in the Department of Neuroscience at The Vickie and Jack Farber Institute for Neuroscience of Sidney Kimmel Medical College, Thomas Jefferson University.
While it’s known that NMDA receptors have a critical role in pathological pain, they also are important to memory and learning; as such they are not good targets for drug interference. The researchers had to find another starting point.
Working with investigators at New York University and the University of Texas at Dallas, the team identified another receptor, ephrin B or EphB2, which gets phosphorylated outside of neurons in response to painful stimuli.
The EphB2 receptor can bind to the NMDA receptor, which modifies the NMDA receptor and pushes it into the synaptic space, a critical junction between nerve cells. The result is an increase in sensitivity to pain. Investigating further, they found by using a chemical that interferes with the EphB2 and NMDA receptor interaction, pain could be blocked.
"Because the protein modification that initiates nerve sensitivity to pain occurs outside of the cell, it offers us an easier target for drug development," Dalva explained. "This is a promising advance in the field of pain management."