Animal Models of Diabetic Neuropathic Pain

Pain is frequently the earliest and most problematic syndrome of distal peripheral neuropathy (DPN) in diabetic patients. The variety of time of onset, duration and progression, modalities, and severity of individual presentations of painful DPN makes classification and evaluation of mechanisms of pain in patients with diabetic neuropathy an outstandingly difficult task. One critical step to address this issue is the need for large-scale prospective studies that start in pain-free prediabetic or diabetic subjects and use questionnaires and neurological bedside and quantitative sensory tests standardized to assess progression of all possible modalities and types of pain. By their nature, however, even the best equipped and designed clinical studies remain mostly observational, and in-depth understanding of human disease is not possible without studies in animal models. Over the past several decades, a wide variety of rodent models of diabetes have been developed and characterized. Progression of DPN in many of these models has also been studied and confirmed, and in this work, we review those data with a specific focus on the utility, challenges, and limitations of using rodent models in research on mechanisms of diabetic pain. Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both (type 1, type 2, and advanced stages of both types of the disease, respectively, (1)). Diabetic neuropathy is defined as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” (2). The most common diabetic neuropathy is distal peripheral neuropathy (DPN, about 70% of all cases (3)); the disease is distinguishable by symmetrical presentation and distal-to-proximal progression of symptoms of sensorimotor impairment. From the combined data on prevalence (Table 1), on average, at least half of patients with DPN have pain as one manifestation of their neuropathy. Furthermore, in about 30% of these cases of painful DPN (PDPN), the pain is graded as severe, in 50% as moderate, and 1. Diabetes, Peripheral Neuropathy, and Pain Chao Ma and Jun-Ming Zhang (eds.), Animal Models of Pain, Neuromethods, vol. 49, DOI 10.1007/978-1-60761-880-5_9, © Springer Science+Business Media, LLC 2011 148 Dobretsov et al. only in 20% as mild (4–6). At the same time, however, in the general community clinic, 35–60% of PDPN patients receive no treatment other than therapy to reduce blood glucose, and the latter unfortunately does not appear to relieve the pain. Moreover, the efficacy of pain-reducing therapies in the remaining cases does not exceed 30–50% of pain reduction (7–11). Development of an optimal treatment strategy requires knowledge of mechanism and natural history of the disease. Furthermore, since it is not possible to predict whether different symptomatic presentations of the disease have common or distinct mechanisms, the natural history of each clinical symptom and sign should be traced back to its onset independently (12–14). Because of the complexity of background disease (diabetes) and difficulty of detection of preclinical diabetes and neuropathy, no symptoms of PDPN has yet received such characterization. Diabetes is a result of slowly progressing deterioration in control of peripheral functions of insulin. The disease passes through an asymptomatic stage of early prediabetes, followed by a stage of moderate fasting and/or postprandial hyperglycemia (advanced prediabetes) and culminates in a state of overt and chronic hyperglycemia (Fig. 1). Once diagnosed, diabetes is treated to normalize blood glucose. Risk of hypoglycemia, however, does not allow complete correction and in terms of glucose metabolism, controlled diabetes is more similar to advanced prediabetes than either normal or overtly diabetic state. Onset of pain may occur at any time following diagnosis of diabetes. Furthermore, pain is a frequently presenting manifestation of neuropathy, leading to discovery and diagnosis of DPN and diabetes or advanced prediabetes in otherwise asymptomatic 2. Natural History and Symptoms of Human PDPN Table 1 Type of diabetes and average prevalencea of clinical DPN Diabetes Prevalence of DPN in diabetes Prevalence of pain in DPN (%) Mean ± SE (number of sources)