The molecular basis of chronic nerve pain in diabetes has been pinpointed in a new study from King’s College London. These findings, in a mouse model, could one day lead to treatments which target the source of the pain.
Around one in four people with diabetes develop a chronic pain condition induced by nerve damage, called painful diabetic neuropathy (PDN), due to high blood sugar. Symptoms include prickling and tingling sensations as well as sharp, shooting pains and extreme sensitivity to touch in the feet and hands, which can spread upward into the legs and arms.
The pain can significantly impair mobility, which in turn exacerbates obesity and worsens type 2 diabetes in a self-perpetuating cycle. Diabetic pain is very difficult to treat and the molecular causes are poorly understood.
This study provides the first evidence that a single type of ion channel known as hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) can by itself be responsible for a complex sensation such as diabetic pain.
The researchers used mouse models of diabetes to show that over-activity of HCN2, which initiates electrical signals in pain-sensitive nerve fibres, results in a sensation of pain. They also found that blocking the activity of HCN2 with Ivabradine, an HCN inhibitor used for treating heart conditions, stopped the sensation of pain entirely.
Furthermore, the researchers performed genetic removal of HCN2 channels in nociceptive neurons and found it prevented development of diabetic pain.
development of diabetic pain.
Obesity And Diabetes
Professor Peter McNaughton, senior author of the study, from the Wolfson Centre for Age-Related Diseases at King’s College London, said:
“The inexorable rise of obesity worldwide, in both rich and poorer countries, has brought a related increase in type 2 diabetes. As many as one in four diabetics suffer from nerve pain, yet there are currently no effective treatments and people therefore typically must resign themselves to a life of continuous suffering. Our study reveals the molecular mechanism driving diabetic pain in mice, which we hope will inform future treatments in people with diabetes.”
Dr Christoforos Tsantoulas, first author of the study, also from the Wolfson Centre for Age-Related Diseases at King’s College London, added:
“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. This research provides a stimulus for the development of targeted pain drugs that can block HCN2 without affecting the activity of other molecules.”
The study was supported by the Medical Research Council, the Biotechnology & Biological Sciences Research Council, and the Wellcome Trust.
Christoforos Tsantoulas, Sergio Laínez, Sara Wong, Ishita Mehta, Bruno Vilar, Peter A. McNaughton
Hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy
Science Translational Medicine 27 Sep 2017: Vol. 9, Issue 409, pp. eaam6072 DOI: 10.1126/scitranslmed.aam6072
Image: left shows nerve fibres (green) in a normal mouse, while the loss of nerve fibres in a diabetic mouse is clearly visible in the image on the right. Credit: King’s College London