Animal Models of Diabetic Neuropathic Pain

Abstract

Diabetic neuropathy is a common complication of diabetes. It occurs in approximately 10–20% of patients with diabetes, or roughly 40–50% patients with diabetic neuropathy. However, the pathogenesis of diabetic neuropathic pain is still largely unknown. Several animal models have been used to study the underlying mechanisms for this complication. Some commonly used animal models include streptozotocin-induced rat and mouse models, diet/nutrition-induced models, combination of chemically- and nutrition-induced model, Zucker diabetic fatty rat model, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rat models, and transgenic/knock-out models. Even though the manifestations of diabetic neuropathic pain vary from thermal or chemical hyperalgesia, thermal or chemical hypoalgeia, allodynia, to spontaneous pain, some pathogenesis factors are shared among these symptoms. Increased AR activity, oxidative-nitrosative stress, protein kinase C, PARP and ACE activations, C-peptide deficiency, impaired neurotrophism, and proinflammatory responses have been identified in the development of diabetic neuropathic pain. This review discusses selected animal models for diabetic neuropathic pain, as well as some commonly shared pathways in these models.

Key words

diabetes - neuropathic pain - animal models

• References

• 1 Bastyr 3rd EJ, Price KL, Bril V. the MBBQ Study Group . Development and validity testing of the neuropathy total symptom score-6: questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy. Clin Ther 2005; 27: 1278-1294
• 2 Beiswenger KK, Calcutt NA, Mizisin AP. Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice. Neurosci Lett 2008; 442: 267-272
• 3 Bennett MI, Attal N, Backonja MM et al. Using screening tools to identify neuropathic pain. Pain 2007; 127: 199-203
• 4 Benstead TJ, Sangalang VE. Nerve microvessel changes in diabetes are prevented by aldose reductase inhibition. Can J Neurol Sci 1995; 22: 192-197
• 5 Bierhaus A, Nawroth PP. Critical evaluation of mouse models used to study pain and loss of pain perception in diabetic neuropathy. Exp Clin Endocrinol Diabetes 2012; 120: 188-190
• 6 Bierhaus A, Fleming T, Stoyanov S et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 2012; 18: 926-933
• 7 Bonner-Weir S, Trent DF, Weir GC. Responses of neonatal rat islet to streptozotocin. Limited B cell regeneration and hyperglycemia. Diabetes 1981; 30: 64-69
• 8 Boulton AJ. The diabetic foot: from art to science. The 18^th Camillo Golgi lecture. Diabetologia 2004; 47: 1343-1353
• 9 Calcutt NA. Potential mechanisms of neuropathic pain in diabetes. Int Rev Neurobiol 2002; 50: 205-208
• 10 Calcutt NA, Freshwater JD, Mizisin AP. Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor. Diabetologia 2004; 47: 718-724
• 11 Cameron NE, Cotter MA, Basso M. Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats. Diabetologia 1997; 40: 271-281
• 12 Cameron NE, Tuck Z, McCabe L et al. Effect of the hydroxyl radical scavenger, dimethylthiourea, on peripheral nerve tissue perfusion, conduction velocity and nociception in experimental diabetes. Diabetologia 2001; 44: 1161-1169
• 13 Cameron NE, Jack AM, Cotter MA. Effect of alpha-lipoic acid on vascular responses and nociception in diabetic rats. Free Radic Biol Med 2001; 31: 125-135
• 14 Cameron NE, Gibson TM, Nangle MR et al. Inhibitors of advanced glycation end product formation and neurovascular dysfunction in experimental diabetes. Ann N Y Acad Sci 2005; 1043: 784-792
• 15 Chaplan SR, Bach FW, Pogrel JW et al. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55-63
• 16 Chen SR, Pan HL. Hypersensitivity of spinothalamic tract neurons associated with diabetic neuropathic pain in rats. J Neuro-physiol 2002; 87: 2726-2733
• 17 Chiechio S, Copani A, Gereau 4th RW et al. Acetyl-L-carnitine in neuropathic pain: experimental data. CNS Drugs 2007; 21 (Suppl 1): 31-38
• 18 Courteix C, Eschalier A, Lavarenne J. Streptozocin-induced diabetic rats: behavioural evidence for a model of chronic pain. Pain 1993; 53: 81-88
• 19 Cotter MA, Jack AM, Cameron NE. Effects of the protein kinase Cb inhibitor LY333531 on neural and vascular function in rats with streptozotocin-induced diabetes. Clin Sci (Lond) 2002; 103: 311-321
• 20 Dobretsov M, Hastings SL, Romanovsky D et al. Mechanical hyperalgesia in rat models of systemic and local hyperglycemia. Brain Res 2003; 960: 174-183
• 21 Dobretsov M, Ghaleb AH, Romanovsky D et al. Impaired insulin signaling as a potential trigger of pain in diabetes and prediabetes. Int Anesthesiol Clin 2007; 45: 95-105
• 22 Devor M, Seltzer S. Pathophysiology of Damaged Nerves in Relation to Chronic Pain. London, England: Churchill Livingstone; 1999
• 23 Diabetes in America 2^nd ed. NIH Publication 95-1468. Washington, DC: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995
• 24 Drel VR, Pacher P, Vareniuk I et al. A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocindiabetic mice. Eur J Pharmacol 2007; 569: 48-58
• 25 Drel VR, Pacher P, Vareniuk I et al. Evaluation of the peroxynitrite decomposition catalyst Fe(III) tetra-mesitylporphyrin octasulfonate on peripheral neuropathy in a mouse model of type 1 diabetes. Int J Mol Med 2007; 20: 783-792
• 26 Eaton SE, Harris ND, Ibrahim S et al. Increased sural nerve epineurial blood flow in human subjects with painful diabetic neuropathy. Diabetologia 2003; 46: 934-939
• 27 Ellis EA, Grant MB, Murray FT et al. Increased NADH oxidase activity in the retina of the BBZ/Wor diabetic rat. Free Radic Biol Med 1998; 24: 111-120
• 28 Francis G, Martinez J, Liu W et al. Intranasal insulin ameliorates experimental diabetic neuropathy. Diabetes 2009; 58: 934-945
• 29 Guberski D, Butler L, Like A. The BBZ/Wor rat: An obese animal with autoimmune diabetes. In: Shafrir E, Renold A. (eds.). Lessons from Animal Diabetes II. London: John Libbe and Company Ltd; 1988: 268-271
• 30 Hall KE, Sima AA, Wiley JW. Voltage-dependent calcium currents are enhanced in dorsal root ganglion neurones from the Bio Bred/Worchester diabetic rat. J Physiol 1995; 486 (Pt 2) 313-222
• 31 Hansson P, Backonja M, Bouhassira D. Usefulness and limitations of quantitative sensory testing: Clinical and research application in neuropathic pain states. Pain 2007; 129: 256-259
• 32 Hemmes RB, Schoch R. High dosage testosterone propionate induces copulatory behavior in the obese male Zucker rat. Physiol Behav 1988; 43: 321-324
• 33 Ilnytska O, Lyzogubov VV, Stevens MJ et al. Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy. Diabetes 2006; 55: 1686-1694
• 34 Islam MS, Choi h. Nongenetic model of type 2 diabetes: a comparative study. Pharmacology 2007; 79: 243-249
• 35 Jafarnejad A, Bathaie SZ, Nakhjavani M et al. Effect of spermine on lipid profile and HDL functionality in the streptozotocin-induced diabetic rat model. Life Sci 2008; 82: 301-307
• 36 Jolivalt CG, Vu Y, Mizisin LM et al. Impaired prosaposin secretion during nerve regeneration in diabetic rats and protection of nerve regeneration by a prosaposin-derived peptide. J Neuropathol Exp Neurol 2008; 67: 702-710
• 37 Jolivalt CG, Lee CA, Ramos KM et al. Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters. Pain 2008; 140: 48-57
• 38 Kage K, Niforatos W, Zhu CZ et al. Alteration of dorsal root ganglion P2X3 receptor expression and function following spinal nerve ligation in the rat. Exp Brain Res 2002; 147: 511-519
• 39 Kalichman MW, Dines KC, Bobik M et al. Nerve conduction velocity, laser Doppler flow, and axonal caliber in galactose and streptozotocin diabetes. Brain Res 1998; 810: 130-137
• 40 Lenzen S. The mechanisms of allxan- and strptozotcin-induced diabetes. Diabetologia 2008; 51: 216-226
• 41 Li F, Drel VR, Szabó C et al. Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy. Diabetes 2005; 54: 1514-1522
• 42 Low PA, Nickander KK, Tritschler HJ. The roles of oxidative stress and antioxidant. Treatment in experimental diabetic neuropathy. Diabetes 1997; 46 (Suppl. 01) S38-S42
• 43 Luo J, Quan J, Tsai J et al. Nongenetic mouse models of non-insulin-dependent diabetes mellitus. Metabolism 1998; 47: 663-668
• 44 Malcangio M, Tomlinson DR. A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain 1998; 76: 151-157
• 45 Meller ST, Pechman PS, Gebhart GF et al. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neuroscience 1992; 50: 7-10
• 46 Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2^nd ed. Seattle, Wa: IASP Press; 1994
• 47 Mondelli M, Aretini A, Baldasseroni A. Distal symmetric polyneuropathy in diabetes. Differences between patients with and without neuropathic pain. Exp Clin Endocrinol Diabetes 2012; 120: 45-50
• 48 Mordes JP, Bortell R, Blankenhorn EP et al. Rat models of type 1 diabetes: Genetics, environment, and autoimmunity. ILAR J 2004; 45: 277-290
• 49 Morrow TJ. Animal models of painful diabetic neuropathy: the STZ rat model. Curr Protoc Neurosci 2004; Chapter 9 Unit 9.18
• 50 Mousa SA, Shaqura M, Khalefa BI et al. Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy. Diabetes 2013; 62: 1308-1319
• 51 Nakamura J, Kato K, Hamada Y et al. A protein kinase C-β-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes 1999; 48: 2090-2095
• 52 Natarajan R, Nadlerm JL. Lipoxygenases and lipid signaling in vascular cells in diabetes. Frontiers in Bioscience 2003; 8 (Suppl. 01) s783-s795
• 53 Natarajan R, Nadler JL. Lipid inflammatory mediators in diabetic vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology 2004; 24: 1542-1548
• 54 Obrosova IG, Drel VR, Oltman CL et al. Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats. Am J Physiol Endocrinol Metab 2007; 293: E1645-E1655
• 55 Obrosova IG, Van Huysen C, Fathallah L et al. An aldose reductase inhibitor reverses early diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense. The FASEB Journal 2002; 16: 123-125
• 56 Obrosova IG, Xu W, Lyzogubov VV et al. PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. Free Radic Biol Med 2008; 44: 972-981
• 57 Obrosova IG. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics 2009; 6: 638-647
• 58 Oltman CL, Davidson EP, Coppey LJ et al. Attenuation of vascular/neural dysfunction in Zucker rats treated with enalapril or rosuvastatin. Obesity (Silver Spring) 2008; 16: 82-89
• 59 Oltman CL, Davidson EP, Coppey LJ et al. Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction. Diabetes Obes Metab 2009; 11: 223-233
• 60 Papanas N, Vinik AI, Ziegler D. Neuropathy in prediabetes: does the clock start ticking early?. Nat Rev Endocrinol 2011; 7: 682-690
• 61 Pittenger GL, Ray M, Burcus NI et al. Intraepidermal nerve fibers are indicators of small fiber neuropathy in both diabetic and non-diabetic patients. Diabetes Care 2004; 27: 1974-1979 69
• 62 Pittenger GL, Mehrabyan A, Simmons K et al. Small fiber neuropathy is associated with the metabolic syndrome. Metabolic Syndrome and Related Disorders 2005; 3: 113-121
• 63 Portha B, Giroix MH, Serradas P et al. Cellular basis for glucose refractoriness of pancreatic B-cells in non insulin dependent diabetes. In Flatt PR, Lenzen S. (eds.). Insulin secretion and pancreatic B cell research. UK: Smith-Gordon; 1994: 461-472
• 64 Qiang X, Satoh J, Sagara M et al. Inhibitory effect of troglitazone on diabetic neuropathy in streptozotocin-induced dia: betic rats. Diabetologia 1998; 41: 1321-1326
• 65 Quattrini C, Harris ND, Malik RA et al. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care 2007; 30: 655-659
• 66 Ramos KM, Jiang Y, Svensson CI et al. Pathogenesis of spinally mediated hyperalgesia in diabetes. Diabetes 2007; 56: 1569-1576
• 67 Reed MJ, Meszaros K, Entes LJ et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 2000; 49: 1390-1394
• 68 Richard S, Jonathan S, Paul Z et al. IDF Diabetes Atlas. fourth edition http://www.idf.org/diabetesatlas Accessed July 28 2013
• 69 Schmidt RE, Dorsey DA, Beaudet lN et al. Analysis of the Zucker Diabetic Fatty (ZDF) Type 2 Diabetic Rat Model Suggests a Neurotrophic Role for Insulin/IGF-I in Diabetic Autonomic Neuropathy. Am J Pathol 2003; 163: 21-28
• 70 Schreiber AK, Neufeld M, Jesus CH et al. Peripheral antinociceptive effect of anandamide and drugs that affect the endocannabinoid system on the formalin test in normal and streptozotocin-diabetic rats. Neuropharmacology 2012; 63: 1286-1297
• 71 Shafrir E, Ziv E, Mosthaf L. Nutritionally induced insulin resistance and receptor defect leading to b cell failure in animal models. Ann NY Acad Sci 1999; 892: 223-246
• 72 Shafrir E. Diabetes in animals: Contribution to the understanding of diabetes by study of its etiopathology in animal models. In: Porte D, Sherwin RS, Baron A. (eds.). Diabetes mellitus. NewYork. McGraw-Hill; 2003: 231-255
• 73 Shun CT, Chang YC, Wu HP et al. Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments. Brain 2004; 127: 1593-1605
• 74 Sima AA, Sugimoto K. Experimental diabetic neuropathy: An update. Diabetologia 1999; 42: 773-788
• 75 Sima AA, Zhang W, Xu G et al. A comparison of diabetic polyneuropathy in type II diabetic BBZDR/Wor rats and in type I diabetic BB/Wor rats. Diabetologia 2000; 43: 786-793
• 76 Siwy J, Zoja C, Klein J et al. Evaluation of the Zucker Diabetic Fatty (ZDF) Rat as a Model for Human Disease Based on Urinary Peptidomic Profiles. PLoS One 2012; 7: e51334
• 77 Srinivasan K, Ramarao P. Animal models in type 2 diabetes research: an overview. Indian J Med Res 2007; 125: 451-472
• 78 Sumner CJ, Sheth S, Griffin JW et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003; 60: 108-111
• 79 Surwit RS, Kuhn CM, Cochrane C et al. Diet-induced type II diabetes in C57BL/6J mice. Diabetes 1988; 37: 1163-1167
• 80 Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physio Res 2001; 50: 536-546
• 81 Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Experimental biology and medicine 2012; 237: 481-490
• 82 Tegeder I, Costigan M, Griffin RS et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med 2006; 12: 1269-1277
• 83 Vareniuk I, Pavlov IA, Obrosova IG. Inducible nitric oxide synthase gene deficiency counteracts multiple manifestations of peripheral neuropathy in a streptozotocin-induced mouse model of diabetes. Diabetologi 2008; 51: 2126-2133
• 84 Velasquez MT, Kimmel PL, Michaelis IV OE. Animal models of spontaneous diabetic kidney disease. FASEB J 1990; 4: 2850-2859
• 85 Vera G, López-Miranda V, Herradón E et al. Characterization of cannabinoid-induced relief of neuropathic pain in rat models of type 1 and type 2 diabetes. Pharmacol Biochem Behav 2012; 102: 335-343
• 86 Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. Pain Med 2008; 9: 660-674
• 87 Vinik AI, Suwanwalaikorn S, Stansberry KB et al. Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve 1995; 18: 574-584
• 88 Vogel HG, Vogel WH.. Drug discovery and evaluation; Pharmacological assays. Heidelberg, Berlin: Springer-Verlag; 1997
• 89 Winzell MS, Ahren B. The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 2004; 53 (Suppl. 03) S215-S219
• 90 WHO Country and regional data on diabetes http://www.who.int/diabetes/facts/world_figures/en/ Accessed November 19, 2013
• 91 Xu X, Liu Z, Liu H et al. The effects of galanin on neuropathic pain in streptozotocin-induced diabetic rats. Eur J Pharmacol 2012; 680: 28-33
• 92 Yagihashi S, Yamagishi SI, Wada RI et al. Neuropathy in diabetic mice overexpressing human aldose reductase and effects of aldose reductase inhibitor. Brain 2001; 124: 2448-2458
• 93 Yan JE, Yuan W, Lou X et al. Streptozotocin-induced diabetic hyperalgesia in rats is associated with upregulation of Toll-like receptor 4 expression. Neurosci Lett 2012; 526: 54-58
• 94 Zhang F, Ye C, Li G et al. The rat model of type 2 diabetic mellitus and its glycometabolism characters. Exp Anim 2003; 52: 401-407
• 95 Zhang JL, Yang JP, Zhang JR et al. Gabapentin reduces allodynia and hyperalgesia in painful diabetic neuropathic rats by decreasing expression level of Nav1.7 and p-ERK1/2 in DRG neurons. Brain Res. 2013; Epub 2012 Nov 23