Scandinavian Journal of Pain 4 (2013) 127128

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Scandinavian Journal of Pain

journal homepage: www.ScandinavianJournalPain.com

Editorial comment

New understanding of mechanisms of painful diabetic neuropathy: A path to prevention and better treatment?
Troels Staehelin Jensen
Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, DK 8000, Aarhus C, Denmark

In this issue of the Scandinavian Journal of Pain Koivisto and Pertovaara [1] point to a new potential mechanism for not only treating hypersensitivity in painful diabetic neuropathy but perhaps also avoiding some of the small ber loss seen in that condition. 1. Immense global burden of diabetes and diabetic polyneuropathy with and without pain Diabetes is a major health and societal problem both in the developed and in the developing world. The International Diabetes Federation (IDF) reports an alarming increase in the number of people with diabetes. According to IDF it is now estimated that more than 371 million people worldwide have diabetes and 4.8 million deaths are directly caused by diabetes. In addition, health care spending on diabetes is about 0.5 trillion U.S. dollars per year (www.idf.org). Both the high death rate and the astronomic cost are largely due to complications of diabetes. Among these complications, diabetic neuropathy is common. Approximately 50% of patients with diabetes (Type I and Type II) develop neuropathy, and in patients with already established diabetic neuropathy up to 60% have painful neuropathy [2,3]. Both for the painful and painless diabetic neuropathy we have been limited to symptomatic treatments except for the strict control of glucose in patients with Type I diabetes. 2. The importance of the family of transient receptor potential ion channels (TRP) for pain and diabetic polyneuropathy Koivisto and Pertovaara have examined one group of the transient receptor potential (TRP) ion channel family: the ankyrin 1 (TRPA1) channel in a series of well-designed studies with important ndings. The TRP family of unspecic ion channels is interesting because several of these compounds are involved in the processing of noxious information. The roles of the TRP vanilloid receptor types 1 and 2 (TRPV1 and TRPV2) have been known for some time; in a number of studies the TRPV1 and TRPV2 have been shown to

mediate the response of capsaicin and to be involved in processing of warm and low pH stimuli [4,5]. However, less has been known about the channels activated by ankyrins. The TRPA are also ion channels expressed on small afferent bers, and cold stimuli activate one of them, the TRPA1 [6]. As pointed out by Koivisto and Pertovaara it is likely that TRPA1 is more involved in pathological cold pain than in processing physiological cold stimuli [1]. This aspect is important because cold allodynia and hypersensitivity to cold is a prominent feature in many neuropathic pain conditions [7,8]. 3. The combination of sensory loss and hypersensitivity in neuropathic pain conditions In painful diabetic neuropathy, as well as in other neuropathic pain conditions, the combination of sensory loss because of reduction of afferent input and the presence of hypersensitivity is a characteristic phenomenon [9,10]. This is present in diabetic neuropathy, although diabetic neuropathic pain conditions are dominated by the loss of input rather than the presence of hypersensitivity phenomena. 4. A TRPA1 antagonist as a disease modifying drug Animal models have been useful to get additional understanding of pathophysiological mechanisms underlying pain. In their studies on painful diabetic neuropathy, Koivisto and Pertovaara used a classical model for diabetes, the streptozocin model, a model for Type I diabetes because streptozocin destroys insulin-producing cells in the pancreas. By administering a selective TRPA1 antagonist (Chembridge5861528) in different ways, they found that TRPA1 expressed by peptidergic small bers contribute to mechanical and cold hypersensitivity in the streptozocin diabetic rats. Interestingly, by pretreating the diabetic rats there were also indication that the TRPA1 antagonist may have a protecting effect on small afferent bers by preventing reduction of these nerve bers both functionally and structurally [11]. They also in their review highlight some of the mechanisms that may be behind this action of TRPA1 in painful diabetic neuropathy. Oxidative stress, which is considered an important factor in the generation of diabetic neuropathy, produces two compounds, methylglyoxal and 4-hydroxynonenal. These compounds

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2012.11.001. Tel.: +45 7846 3380; fax: +45 7846 3269. E-mail address: tsjensen@ki.au.dk

1877-8860/$ see front matter 2013 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sjpain.2013.04.004

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have been demonstrated to activate the TRPA1 channel and therefore it is likely that such reactive compounds produced in Type I diabetes may contribute to the development of painful diabetic neuropathy. 5. Impaired insulin signaling, dyslipidaemia, metabolic syndrome contribute to painful diabetic neuropathy Does this then mean that the mechanism of painful diabetic neuropathy (PDN) is solved and that we now have compounds that can modify the disease rather than just treat its symptoms? No, we are denitely not there yet. First, there are several other mechanisms involved in the generation of diabetic neuropathy beside methylglyoxal and 4-hydroxynonenal [3]. For example, dyslipidaemia, impaired insulin signaling, and the metabolic syndrome all contribute to the development of diabetic neuropathy. The molecular mechanisms behind these phenomena include a series of other mechanisms than methylglyoxal and 4-hydroxynonenal for review see [12]. Also as pointed out by Koivisto and Pertovaara, the streptozocin model has limitations: it is a model for Type I diabetes, and the signs of neuropathy occur within days to weeks in the animal models whereas the clinical neuropathy takes years to develop. Type II diabetes is now the main reason for the increase of diabetes worldwide, and there are currently no known treatments to reduce the development of neuropathy and prevent the development of pain in this group of patients. 6. Important implications for pain clinicians and patients of the TRPA1 research by Koivisto and Pertovaara Despite the above limitations, the studies by Koivisto and Pertovaara are interesting and refreshing. They touch on a conundrum that pain researchers and clinicians are struggling with every day: we need to get to a point where we, on a basis of understanding the underlying mechanisms of diseases and pain, can in fact modify or

even better, cure disease and its associated pain rather than just treating the symptoms [13,14]. References
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