Jump-Starting the Body’s Own Opioid System to Ease Painful Diabetic Neuropathy

Diabetic neuropathy

A new study in mice shows that endogenous opioids – the body’s natural pain relievers – in peripheral nerves contribute to pain from nerve damage in diabetes. A similar mechanism may be at play in people. Image credit: designer491/123RF Stock Photo.

Published July 9, 2021

Editor’s note: This story first appeared on the IASP Pain Research Forum and has been edited for RELIEF.

Pain from the nerve damage often seen in people with diabetes (painful diabetic neuropathy) remains a stubborn problem for many patients. Previous research in rodents and people has shown that changes in endogenous opioids – the body’s own natural pain relievers – in the central nervous system contribute to this painful condition.

But opioids are active in the peripheral nervous system (outside of the brain and spinal cord) too. Could that also contribute to painful diabetic neuropathy? A new study says yes, with important implications for treating people with the disease.

The new research, from Peter Nawroth, University Hospital of Heidelberg, Germany, and colleagues reveals that opioid signaling in the peripheral nervous system is impaired in a mouse model of diabetic neuropathy, which contributed to pain in the animals.

Further, restoring opioid signaling in nerve cells reversed neuropathic pain in the mice. Experiments in patients with diabetic neuropathy showed that impaired opioid signaling may play a role in humans too.

“This paper is very important for how we understand the organism’s own ability to control pain,” said Claudia Sommer, a pain physician and researcher at the University of Würzburg, Germany, “If you can do something to increase the organism’s own ability to reduce neuropathic pain, this might be a very efficient treatment for it,” according to Sommer, who was not involved in the new work.

The study appeared in Nature Communications on January 18, 2021.

A problem with the opioid system
The researchers first discovered that proopiomelanocortin (POMC), a protein in brain neurons that can be broken down into an endogenous opioid, was also present in the peripheral nervous system in healthy adult mice, including in nociceptors.

Nociceptors are nerve cells that detect potentially dangerous stimuli – think a hand on a hot stove or a pinprick – and then relay information about those stimuli into the central nervous system, potentially culminating in an experience of pain. That POMC was present in the nociceptors suggested it could play a role in modulating pain.

“It was quite shocking, and it took a few months for us to get over the initial skepticism. Until now it was believed that the neurons that produced POMC were in only the central nervous system, but our findings showed that POMC is also expressed in the peripheral nervous system,” said Divija Deshpande, first author of the study.

The researchers had shown the presence of POMC in nerve cells of the peripheral nervous system, under normal conditions. But what was happening during diabetic neuropathy? To find out, the investigators turned to their mouse model of the condition.

As expected, these mice showed increased pain sensitivity. They also had lower levels of both POMC and of the mu-opioid receptor, a protein to which opioids attach, in peripheral neurons. This showed that the endogenous opioid system was not working properly in the diabetic mice, which could contribute to their neuropathic pain.

Providing a boost relieves diabetic neuropathy in mice – and perhaps one day in people too
The team next tested if fixing the faulty endogenous opioid system could ease diabetic neuropathic pain in their mouse model.

To do so, they used a harmless virus (a common experimental approach in biology) to increase the amount of POMC and μ-opioid receptors in neurons of the diabetic mice.

Impressively, boosting the endogenous opioid system in this way reduced neuropathic pain in the diabetic animals.

All the research so far had taken place in mice. But what about people? Did the animal findings have any relevance to human diabetic neuropathy?

To find out, the authors looked at the sciatic nerves from patients with type 1 and type 2 diabetes. It turned out that these nerves had decreased amounts of both POMC and of the mu-opioid receptor, compared to healthy controls. This showed that the findings in mice had relevance to what happens in people with diabetic neuropathy.

Overall, the results from the new study suggest that boosting endogenous opioids in the peripheral nervous system could be a way to help people with diabetic neuropathy, and other neuropathies, in the future.

“If we could target the opioid system peripherally to effectively treat neuropathic pain, that would be a big advantage. This would avoid central nervous system side effects of opioids, including addiction and tolerance,” Sommer said.

However, according to Thomas Fleming, one of the study authors, exactly how best to do so remains unclear.

“The problem is how to translate the idea of targeting the peripheral opioid system to treat neuropathic pain in humans,” Fleming said. “We used a viral approach to boost POMC production in [peripheral sensory neurons] in rodents, but this isn’t possible yet in humans. The trick is to do this in a non-invasive way, and technologies are getting there.”

Fred Schwaller, PhD, is a freelance science writer based in Germany.