Researchers are hopeful they have identified a new way to treat chronic pain caused by arthritis, shingles, and nerve damage.
They’ve discovered a compound that can dampen activity of an enzyme called PIP5K1C, which controls the activity of cellular receptors that signal pain. Reducing the level of the enzyme eases the levels of a crucial lipid called PIP2 in pain-sensing neurons, decreasing pain.
The creation of such bodily pain might seem simple, but at the cellular level it’s quite complex.
When we’re injured, a diverse mixture of chemicals is released, and these chemicals cause pain by acting on an equally diverse group of receptors on the surface of pain-sensing neurons.
“A big problem in our field is that it is impractical to block each of these receptors with a mixture of drugs,” says Mark Zylka, associate professor of cell biology and physiology at UNC School of Medicine. “So we looked for commonalities—the things that each of these receptors need in order to send a signal.”
Finding pain commonalities
The lipid PIP2 was one of these commonalities.
“So the question became: how do we alter PIP2 levels in the neurons that sense pain?” Zylka says. “If we could lower the level of PIP2, we could get these receptors to signal less effectively. Then, in theory, we could reduce pain.”
Many different kinases can generate PIP2 in the body. Brittany Wright, a graduate student in Zylka’s lab, found that the PIP5K1C kinase was expressed at the highest level in sensory neurons compared to other related kinases. The researchers then used a mouse model to show that PIP5K1C was responsible for generating at least half of all PIP2 in these neurons.
Wright is first author of the paper that is published in the journal Neuron.
“That told us that a 50 percent reduction in the levels of PIP5K1C was sufficient to reduce PIP2 levels in the tissue we were interested in—where pain-sensing neurons are located,” Zylka says. “That’s what we wanted to do—block signaling at this first relay in the pain pathway.”
Once Zylka and colleagues realized that they could reduce PIP2 in sensory neurons by targeting PIP5K1C, they teamed up with Stephen Frye, director of the Center for Integrative Chemical Biology and Drug Discovery at the UNC Eshelman School of Pharmacy.
They screened about 5,000 small molecules to identify compounds that might block PIP5K1C. There were a number of hits, but UNC3230 was the strongest with good potential as a drug candidate. The chemical structure of the molecule can be manipulated to potentially turn it into an even better inhibitor of PIP5K1C. Experiments to do so are now under way.
The National Institute of Neurological Disorders and Stroke funded the study.
Source: UNC-Chapel Hill