Pain from Damaged Nerves in Diabetes: Where Does It Come From?

Pain from diabetic neuropathy

Researchers find that a protein called HCN2 increases pain in diabetic mice. Image credit: medeja/123RF Stock Photo.

Diabetes is on the rise, and consequently, so is the persistent and often intractable pain experienced by many diabetic patients with nerve damage (known as painful diabetic neuropathy; see related RELIEF feature). Researchers, however, still have a poor grasp of the source of that pain, making it difficult for them to design better treatments.

But now, a team led by Peter McNaughton at King’s College London identifies a protein, called HCN2, that lowers the threshold for pain in experimental models of diabetes. The researchers used genetically modified mice that lack HCN2 but only in pain-sensing neurons. While these animals showed clear signs of diabetes and nerve damage, they did not become hypersensitive to touch, in contrast to their genetically unaltered counterparts. Hypersensitivity to touch is also seen in people suffering from diabetic neuropathy.

“If the results translate to humans, this would mean that HCN2 is a new target for analgesia [pain relief] in painful diabetic neuropathy, and that pain in diabetes could be treated in the peripheral [outside of the brain and spinal cord] nervous system,” says Claudia Sommer, a pain researcher and physician at the University of Würzburg in Germany. “Thus drugs with central nervous system side effects would not be needed,” according to Sommer, who was not involved in the study.

The results were published September 27 in the journal Science Translational Medicine.

The path to HCN2
HCN2 is part of a family of four pore-shaped proteins known as HCN channels. The proteins act like pacemakers, controlling the rate at which cells, including pain-sensing neurons, generate electrical signals. When HCN channels become more active, so do the neurons they are embedded in.

As a result, researchers have long thought that HCN channels might drive chronic pain. “There had been some indications, from 2003 onwards, that blockers of HCN channels—drugs that block all four types indiscriminately—were quite effective analgesics,” says McNaughton. And so, “I wondered which one of the four channels might be involved” in pain.

In 2011, his lab converged on an answer. Unlike what was seen with normal mice, animals that had been genetically engineered to lack HCN2 in pain neurons did not develop long-lasting pain after their nerves were experimentally injured.

“We found that HCN2 was the criminal, so to speak,” says McNaughton.

Even so, for Christoforos Tsantoulas, lead author of the new study, the relevance of the discovery for patients with painful diabetic neuropathy was unclear. He wondered if pain could also be prevented when nerve damage is caused instead by a disease, like diabetes, rather than by an experimental nerve injury.

Improving pain in diabetic mice
To address this concern, the researchers injected mice with streptozotocin (STZ). This chemical kills insulin-producing cells in the pancreas, and as a result, raises blood sugar levels. Animals that receive STZ are a model of type 1 diabetes, which similarly involves the loss of insulin.

When the researchers then gave these diabetic mice ivabradine, a drug that interferes with all four versions of HCN channels (but does not get into the central nervous system), they saw a decrease in pain hypersensitivity. Better still, eight doses delivered over four days completely reversed it.

A mouse model of type 2 diabetes yielded similar results. This was an important finding since type 2 diabetes is far more common in people than type 1.

Next, the group turned to the genetically modified mice used in their 2011 study—the ones missing HCN2 in their pain neurons. In these animals, STZ caused diabetic neuropathy, as expected, but not pain. This suggested that, of all four HCN proteins, HCN2 was again the primary culprit.

Be selective
Ivabradine is already prescribed for chest pain and congestive heart failure in people, so could it be repurposed for painful diabetic neuropathy? McNaughton is doubtful, since it would affect not only HCN2 but also HCN4, which is present in the heart.

That means only low doses of the drug would be safe for use in patients. “I wouldn’t be surprised if these doses are not that effective” for painful diabetic neuropathy, says McNaughton.

“What you really need to do is to block HCN2 selectively,” he says. “From a clinical point of view, it’s a much more desirable way to go.”

To read about the research in more detail, see the related IASP Pain Research Forum news story here.

Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman