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 new study published in Science Translational Medicine provides the first evidence that a HCN2 channel- 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 channels, which initiates electrical signals in pain-sensitive nerve fibres, results in a sensation of pain. They also found that blocking the activity of HCN2, or removing it completely from pain-sensitive nerve fibres, stopped the sensation of pain entirely.
Authors also found that intracellular cyclic adenosine monophosphate (cAMP), a positive HCN2 modulator, is increased in somatosensory neurons in an animal model of painful diabetes. They propose that the increased intracellular cAMP drives diabetes-associated pain by facilitating HCN2 activation and consequently promoting repetitive firing in primary nociceptive nerve fibers.
The senior author of the study 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.'
The first author of the study said: '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.'
https://www.kcl.ac.uk/ioppn/news/records/2017/September/Researchers-uncover-the-source-of-diabetic-pain.aspx
http://stm.sciencemag.org/content/9/409/eaam6072
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