Drugs that block a protein called HCN2 may have the potential to provide much-needed relief for people with diabetes who have chronic nerve pain.
So concludes a study by researchers from King’s College London in the United Kingdom, who report their work in the journal Science Translational Medicine.
The global burden of diabetes
Many people with the condition experience diabetic nerve pain – that is, a chronic disorder that results from diabetic neuropathy, which is a type of nerve damage caused by high blood sugar.
Diabetic nerve pain is a complex condition with several symptoms that can include sharp shooting pains, tingling and prickling sensations, and extreme sensitivity to touch. The symptoms often start in the hands and feet before spreading up into the arms and legs.
The pain can be so bad that it impairs mobility, causing people to gain weight, which worsens the effects of diabetes and so sets up a vicious cycle.
“As many as 1 in 4 diabetics suffer from nerve pain,” comments senior author Peter McNaughton, a professor in the Wolfson Centre for Age-Related Diseases at King’s College London. “Yet there are currently no effective treatments and people therefore typically must resign themselves to a life of continuous suffering.”
In their study paper, he and his colleagues also explain that the molecular biology of diabetic nerve pain is poorly understood, so they summarize what has been discovered so far.
The nerve damage that occurs in diabetes interferes with the body’s ability to detect painful stimuli, or nociception.
Normally, nociception triggers valuable signals that warn against imminent damage. In diabetic nerve pain, however, the damaged nerves cause the signals to persist, even in the absence of threats.
Because diabetic nerve pain arises from damage to the sensory nerves, it does not respond to many drugs that work in other types of pain, creating a desperate need for new pain drugs.
In the new study, the team investigated the role that a protein called hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) might play in giving rise to diabetic nerve pain.
The protein belongs to a group called HCN that act as “ion channels” – that is, proteins that make tiny holes in cell membranes that allow electrically charged ions to pass through.
Previous research has shown that HCN ion channels have an important pacemaker role in the heart.
It has also been suggested that they may act as a “pacemaker for pain,” and that, by maintaining electrical activity in pain-sensitive nerve fibers, or nociceptive neurons, they give rise to the “sensation of chronic pain in pathological pain states.”
Using mouse models of diabetes, the team confirmed that this is what happens. They showed that overactive HCN2 triggers and maintains electrical signals in nociceptive neurons and thus promotes the sensation of pain, even in the absence of a threat.
The researchers also found that blocking HCN2 channels, or “genetically deleting” them in small nociceptive neurons, completely stopped the sensation of pain.
“At present we do not have selective drugs which can suppress the activity of HCN2 without affecting other bodily functions, such as the regulation of heart rate,” explains first author Dr. Christoforos Tsantoulas, also from the Wolfson Centre for Age-Related Diseases.
The team hopes that the findings will spur the development of pain drugs that selectively target HCN2 without disturbing other molecules.
“Our results suggest that HCN2 may be an analgesic target in the treatment of painful diabetic neuropathy.”