Treating Chronic Pain

UNC-TV Science: July 9, 2014
New Compound May Help Treat Chronic Pain

Arthritis affects more than 52 million American adults. Americans spend more than $50 billion on back pain every year. While both chronic conditions present with the same symptom, pain, they actually have two very different underlying causes, each tricky to manage.

New research from the UNC School of Medicine, however, has highlighted an area where both conditions and others like them behave the same way. The researchers also developed a compound that, in mice, takes advantage of that similarity to treat both.

Pain is the result of a signal from a specific type of neuron called a nociceptor. When you step on a nail, the damaged tissue releases a host of different signaling chemicals. When the nociceptor receives any one these signals, it passes a message through your leg, to your spine and into your brain telling you that your foot has a hole in it. Your brain translates this into a feeling of pain and you stop stepping on the nail. Each chemical signal has its own nociceptor to look for it.

That single “ouch” moment is called acute pain. But chronic pain, which lasts for a long time, is a little different and can be caused one of two ways. Inflammatory pain, like in arthritis, comes again from chemicals released by the surrounding tissue. The chronic inflammation of an arthritic joint spews chemical signals that act on a wide variety of nociceptors all day, every day.

But sometimes the nerves themselves get damaged, and this is called neuropathic pain. The nerves themselves send an S.O.S. to the brain, which gets translated as pain. Shingles and chronic back pain both exhibit damaged nerves.

The trouble is that all the different varieties of nociceptors involved in inflammation and the different types of damage in neuropathy make treating pain at the source, well... a pain. Shutting down damaged nerves or specific nociceptors one at a time or with a cocktail of different drugs is unwieldy and has the potential to turn off nerves that aren’t actually causing any harm.

One way to bypass this is to alter the brain’s chemistry, thereby changing how it processes signals. That’s how narcotic painkillers work. Doctors often treat inflammatory pain by attacking the inflammation itself, with over the counter drugs like ibuprofen, acetaminophen, and naproxen.

But many scientists still search for ways to treat chronic pain through the nerves by finding ways to treat multiple painful nerves. Mark Zylka, a cell biologist at the UNC School of Medicine, figured that if we can’t practically stop the pain right at the nociceptor endings, perhaps we could by moving slightly downstream. Nociceptors have to pass their pain signal along through proteins and other cells. Zylka found that one particular protein, called PIP5K1C is a common stop on the path from inflammatory and neuropathic pain. PIP5K1C makes an important compound called PIP2, which allows a nociceptor to send a pain signal. Lots of proteins make PIP2, but in sensory neurons PIP5K1C makes more of it than any other protein.

The thinking goes, then, dampen PIP5K1C, make less PIP2, feel less pain. Zylka tested this theory in mice. He injected pain signal chemicals into both normal mice and genetically modified mice with half the PIP5K1C they were supposed to have. He saw that the PIP5K1C-depleted mice exhibited much less pain behavior and were slower to react to painful stimuli. Essentially, the PIP5K1C-depleted mice felt less pain than the normal ones.

With some help from researchers at the UNC School of Pharmacy, Zylka then screened more than 5000 compounds to find one that best halted the function of PIP5K1C. The winning compound was one made by Stephen Frye, director of the School of Pharmacy, called UNC3230. Tests are currently underway to refine UNC3230 into an even better inhibitor of PIP5K1C that could maybe one day be used as a treatment for chronic pain of all stripes.

The paper describing this work was published in the journal Neuron.

- Daniel Lane

Daniel Lane covers science, medicine and the environment as a reporter/writer. He is currently pursuing a master's degree in medical and science journalism at UNC - Chapel Hill.

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