Stop the pain before it starts

UNC researchers have discovered a new target for chronic pain treatment.

June 24th, 2014

Between 50 and 100 million Americans suffer daily from chronic pain, yet there are a limited number of drugs available for treating it. “We have drugs that are outstanding for stopping acute pain, like the pain a patient would experience after surgery,” says Mark Zylka, a researcher at the UNC School of Medicine. “But for long-term, chronic pain, there really aren’t that many drugs.”

To understand how different drugs help relieve different kinds of pain, it helps to first understand what happens inside the body when you get hurt. Let’s say you fall off your bike and break your arm. There will be redness and swelling around the site of the injury, and that area will become sensitive (i.e. painful) because of a release of chemicals that activate receptors on the surface of pain-sensing neurons.

You go to the hospital, get your arm put in a cast, and then you take a painkiller, like Vicodin or oxycodone. The opioids in those drugs bind to the receptors so that you no longer feel pain. Your arm starts to heal, the pain goes away, and you no longer need to take the receptor-blocking drugs. That’s acute pain.

But what if your arm still hurts six months after the cast comes off? Then it may be considered chronic pain, where the sensitivity response outlasts the stimulus, according to Zylka. Your body tissues can continue to release the chemicals that activate pain-sensing neurons long after the injury takes place.

Chronic pain is considered a disease, and people suffering from it have to take drugs for long periods of time—often years. As time goes on, those drugs begin to lose their effectiveness. “The patient then has to take a higher dose of the same drug, or switch to a stronger drug, and that’s when serious side effects start to show up,” Zylka says. “So there’s a big push in the field now to find additional ways of treating chronic pain.”

It comes down to the activation of the pain signaling receptors. If you picture the pain response in your body as a relay race, the sensitization response would be the first hand-off. Zylka says he and his team were looking for a way to block signaling at this first relay in the pain pathway. “We know that active receptors signal through a lipid called PIP2, so we looked at ways of reducing the level of PIP2 in these pain-sensory neurons.”

Many different kinases, or enzymes, 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. Then the researchers used a mouse model to show that PIP5K1C was responsible for generating at least half of all PIP2 in these neurons.

So if they could find a way to block PIP5K1C from making PIP2, then they could lower the levels of PIP2 in the body and thereby decrease the sensitivity response. To do that, they needed to find an inhibitor that could block PIP5K1C.

Zylka went to Stephen Frye at UNC’s Eshelman School of Pharmacy. Frye is the go-to researcher when it comes to finding inhibitors. “He used to work at Glaxo, where he developed three different kinase inhibitors that are now being used to treat cancer, so he’s an expert when it comes to finding drugs to block kinases,” Zylka says. They screened about 5,000 small molecules to identify compounds that might block PIP5K1C. There were a number of hits, but the strongest was a new compound they named UNC3230.

Their findings were published in the journal Neuron in May. While the effectiveness of the compound is promising, there are still years of research to come. First, Zylka and Frye must get the compound into a soluble form so that it can be run through all the preclinical tests before going to clinical trials. “We’re trying to make better drugs that target PIP5K1C,” Zylka says. “Right now, that’s the best one we have.”

Mark Zylka is an associate professor of cell biology and physiology and is in the UNC Neuroscience Center. Brittany Wright graduated from the UNC Eshelman School of Pharmacy in 2013. She was the first author on the Neuron Paper. Along with Zylka and Frye, other authors include Jian Jin, associate director of the center for integrative chemical biology and drug discovery, and William Janzen, director of assay development and compound profiling in the Center for Integrative Chemical Biology and Drug Discovery.