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Seeking Better Treatment for Nerve Damage

Nigel Calcutt, PhD
Photography by Corinne Jolivalt/University of California–San Diego

Nigel Calcutt, PhD

Occupation
Professor in the Department of Pathology at the University of California–San Diego

Focus
Pathology

American Diabetes Association Research Funding
Clinical Translational Research

If you’ve had diabetes for a while, you may be familiar with the sensations that come with diabetic nerve damage. To you, dying or dysfunctional nerves might cause burning, painful sensations at the slightest touch; for others, the complication might manifest as numbness. It’s felt most often in the hands and feet, parts of the body that have a high density of sensory nerve endings to tell us about our environment.

Nerve damage—doctors call it neuropathy—is a common complication of both type 1 and type 2 diabetes, ultimately affecting about half of all people with diabetes. For about half of those with diabetic neuropathy, the nerve damage results in numbness. That can be dangerous: With no nerves to prompt pain and set off alarms, small cuts can get infected and grow into major wounds. “Pain is actually a good thing. It [acts] as a protection mechanism,” says Nigel Calcutt, PhD, a neuroscientist and professor in the Department of Pathology at the University of California–San Diego. “It tells you when you’re getting injured.”

But sometimes pain isn’t quite so useful. That’s the case for people with the painful kind of diabetic neuropathy. They feel pain, but a kind that’s often misdirected. Their pain seems to come from things that ordinarily wouldn’t hurt: A burning sensation from the lightest touch, such as bedsheets or clothes resting on the skin, is a common complaint. “What we have in diabetes is pain that isn’t useful anymore,” says Calcutt. Treating this mystery pain is tricky, too. Commonly prescribed pain medications, including opiates and other heavy-duty painkillers, often don’t work on diabetic neuropathy.

Why damaged nerves would cause pain is one of diabetic neuropathy’s perplexing mysteries. When Calcutt began researching painful neuropathy more than 25 years ago, most researchers believed that the answer lay in the toes and fingers of the people affected. “The general assumption was that when your hand hurts, that’s where the problem is,” Calcutt says. Studies focused on trying to figure out what was happening at the nerve endings in hopes of finding a cure for the pain. The operating assumption was that nerves damaged by diabetes were compensating by sending even stronger signals to the spinal cord, which were then transmitted to the brain as pain.

But Calcutt wondered if there might be something going on further up the line. The nerves in your fingers and toes are the first link in a chain connecting to the spinal cord. The nerves in the spinal cord then relay signals to the brain and back again. All this intercellular communication relies on chemical signals. “We looked at the way nerves communicate with the spinal cord,” Calcutt says.

When he began looking at the interaction between nerves and the spinal cord, he found that the chemical communication was more muted than what he saw in healthy nerves.

And, Calcutt and his team found, levels of an important chemical that normally dials down signals inside the spinal cord were higher in animals with diabetes. “The stimulating ones went down instead of up, and the inhibitory ones were going up instead of down,” he says. Surprisingly, the normally inhibitory chemicals in the spinal cord were now causing pain, not blocking it.

Around the same time, a colleague sent him a remarkable case study: A man who had a leg amputated as a child developed diabetes in middle age. When he began experiencing painful neuropathy, the man felt it in both his remaining foot and the one he’d lost as a child, over 40 years earlier. “It showed me diabetes can cause pain where you haven’t even got the limb,” Calcutt says. “That changed our thinking. The problem wasn’t just in the periphery, and the injury doesn’t have to be in the hands and feet for pain to be perceived in the hands and feet.”

The discoveries convinced him that for some people, painful diabetic neuropathy is a result of something that’s gone wrong in the nerves of the spinal cord, not the fingers or toes. He’s even worked out a possible test for the chemical transmitter imbalances, based on experiments in animals with diabetic neuropathy.

With the help of a grant from the American Diabetes Association, Calcutt is working with Andrew Marshall, MD, a neuroscientist at the University of Manchester in the United Kingdom, to see if a simple test using electrical current to stimulate nerves—a variant of those already used to check for neuropathy—can separate people with type 2 diabetes whose pain is the result of spinal cord problems from people with type 2 whose pain is coming from the nerves in the hands and feet.

The test would open up a new possibility: personalized medicine for neuropathic pain. If doctors could easily see what transmitters are working properly and whether the problem is in a patient’s spinal cord or elsewhere, their treatment could be tailored to address the problem directly. “In any given patient, we could do the test and say, ‘We think the pain is coming from the spinal cord and these are the medications that work best,’ ” Calcutt says. “Once we know, we can design better drugs.”

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