Effects of Melatonin and Vitamin E on Peripheral Neuropathic Pain in Streptozotocin-Induced Diabetic Rats

Document Type: Original Article

Authors

Department of Biology, Faculty of Sciences, Urmia University, Urmia, Iran

Abstract

Objective(s)
Previous studies have indicated that diabetes mellitus might be accompanied by neuropathic pain. Oxidative stress is implicated as a final common pathway in development of diabetic neuropathy. Pharmacological interventions targeted at inhibiting free radical production have shown beneficial effects in diabetic neuropathy. The aim of this study was to investigate and compare the possible analgesic effects of melatonin and vitamin E in diabetic rats.
Materials and Methods
This study was performed on 32 male Wistar rats divided into 4 groups: control, diabetic, melatonin-treated diabetic and vitamin E-treated diabetic. Experimental diabetes was induced by intraperitoneal streptozotocin (50 mg/kg) injection. Melatonin (10 mg/kg, i.p.) and vitamin E (100 mg/kg, i.p.) were injected for 2 weeks after 21st day of diabetes induction. At the end of administration period, pain-related behavior was assessed using 0.5% formalin test according to two spontaneous flinching and licking responses. The levels of lipid peroxidation as well as glutathione-peroxidase and catalase activities were evaluated in lumbosacral dorsal root ganglia.
Results
Formalin-evoked flinching and total time of licking were increased in both acute and chronic phases of pain in diabetic rats as compared to control rats, whereas treatment with melatonin or vitamin E significantly reduced the pain indices. Furthermore, lipid peroxidation levels increased and glutathione-peroxidase and catalase activities decreased in diabetic rats. Both antioxidants reversed the biochemical parameters toward their control values.
Conclusion
These results suggest that oxidative stress may contribute to induction of pain in diabetes and further suggest that antioxidants, melatonin and vitamin E, can reduce peripheral neuropathic pain in streptozotocin-induced diabetic rats.

Keywords


1.Baynes JW, Thorpe R. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999; 48:1-9.

2.Robertson RP. Chronic oxidative stress: a central mechanism for glucose toxicity in pancreatic islet beta cell in diabetes. J Biol Chem 2004; 279:42351-42354.

3.Wolff SP, Dean RT. Glucose auto-oxidation and protein modification. The potential role of antioxidative glycosylation in diabetes. Biochem J 1987; 245:243-250.

4.Klepac N, Rudes Z, Klepac R. Effect of melatonin on plasma oxidative stress in rats with streptozotocin induced diabetes. Biomed Pharmacother 2006; 60:32-35.

5.Serpell M. Anatomy, physiology and pharmacology of pain. Anaesth Intensive Care Med 2005; 6:7-10.

6.Calcutt NA. Potential mechanisms of neuropathic pain in diabetes. Int Rev Neurobiol 2002; 50:205-228.

7.Morgan PJ, Barrett P, Howell HE, Helliwell R. Melatonin receptors: localization, molecular pharmacology and physiological significance. Neurochem Int 1994; 24:101-146.

8.Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a nerve-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007; 42:28-42.

9.Allegra M, Reiter RJ, Tan DX, Gentile C, Tesoriere L, Livrea MA. The chemistry of melatonin's interaction with reactive species. J Pineal Res 2003; 34:1-10.

10.Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, et al. Regulation of antioxidant enzymes: A significant role for melatonin. J Pineal Res 2004; 36:1-9.

11.Hong JH, Kim MJ, Park MR, Kwag OG, Lee IS, Byun BH, et al. Effects of vitamin E on oxidative stress and membrane fluidity in brain of streptozotocin-induced diabetic rats. Clin Chim Acta 2004; 340:107-115. 

12.Baydas G, Canatan H, Turkoglu A. Comparative analysis of the protective effects of melatonin and vitamin E on streptozotocin-induced diabetes mellitus. J Pineal Res 2002; 32:225-230.

13.Kim HK, Kim JH, Gao X, Zhou JL, Lee I, Chung K, et al. Analgesic effect of vitamin E is mediated by reducing central sensitization in neuropathic pain. Pain 2006; 122:53-62.

14.Arreola-Espino R, Urquiza-Marin H, Ambriz-Tututi M, Araiza-Saldana CI, Caram-Salas NL, Rocha-Gonzalez HI, et al. Melatonin reduces formalin-induced nociception and tactile allodynia in diabetic rats. Eur J Pharmacol 2007; 577:203-210.

15.Malone JI, Lowitt S, Korthals JK, Salem A, Miranda C. The effect of hyperglycemia on nerve conduction and structure is age dependent. Diabetes 1996; 45:209-215.

16.Tuzcu M, Baydas G. Effects of melatonin and vitamin E on diabetes-induced learning and memory impairment in rats. Eur J Pharmacol 2006; 537:106-110.

17.Montilla P, Cruz A, Padilla FJ, Tunez I, Gascon F, Munoz MC, et al. Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats. J Pineal Res 2001; 31:138-144.

18.Juarez-Rojop IE, Granados-Soto V, Diaz-Zagoya JC, Flores-Murrieta FJ, Torres-Lopez JE. Involvement of cholecystokinin peripheral nociceptive sensitization during diabetes in rats as revealed by the formalin response. Pain 2006; 122:118-125.

19.Wheeler-Aceto H, Cowan A. Standardization of the rat paw formalin test for the evaluation of analgesics. Psychopharmacology 1991; 104:35-44.

20.Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977; 4:161-174.

21.Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: malonaldehyde and 4- hydroxynonenal. Methods Enzymol 1990; 186:407-421.

22.Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium deficient rat liver. Biochem Biophys Res Commun 1976; 71:952-958.

23.Aebi H. Catalase in vitro. Method Enzymol 1984; 105:121-126.

24.Lowry OH, Rosebrough NJ, Farr AL, Randal RJ. Protein measurement with Folin phenol reagent. J Biol Chem 1951; 193:265-275.

25.Low PA, Nickander KK, Tritschler HJ. The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. Diabetes 1997; 46:38-42.

26.Hawkins CL, Davies MJ. Generation and propagation of radical reactions on proteins. Biochem Biophys Acta 2001; 1504:196-219.

27.Baydas G, Sonkaya E, Tuzcu M, Yasar A, Donder E. Novel role for gabapentin in neuroprotection of central nervous system in streptozotocin-induced diabetic rats. Acta Pharmacol Sin 2005; 26:417-422.

28.Van Dam PS, Van Asbeck BS, Bravenboer B, Van Oirschot JF, Gispen WH, Marx JJ. Nerve function and oxidative stress in diabetic and vitamin E-deficient rats. Free Radic Biol Med 1998; 24:18-26.

29.Halat KM, Dennehy CE. Botanicals and Dietary Supplements in Diabetic Peripheral Neuropathy. J Am Board Fam Pract 2003; 16:47-57.

30.Kishi M, Tanabe J, Schmelzer JD, Low PA. Morphometry of dorsal root ganglion in chronic experimental diabetic neuropathy. Diabetes 2002; 51:819-824.

31.Kishi Y, Nickander KK, Schmelzer JD, Low PA. Gene expression of antioxidant enzymes in experimental diabetic neuropathy. J Peripher Nerv Syst 2000; 5:11-8.

32.Schmeichel AM, Schmelzer JD, Low PA. Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. Diabetes 2003; 52:165-171.

33.Siu AW, Reiter RJ, To CH. The efficacy of vitamin E and melatonin as antioxidants against lipid peroxidation in rat retinal homogenates. J Pineal Res 1998; 24:239-244.

34.Ziegler D,Gries FA. a-Lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes 1997; 46:62-66.

35.Vissers KG, Geenen F, Biermans R, Meert TF. Pharmacological correlation between the formalin test and the neuropathic pain behavior in different species with chronic constriction injury. Pharmcol Biochem Behav 2006; 84:479-486.

36.Sayyed SG, Kumar A, Sharma SS. Effects of U83836E on nerve functions, hyperalgesia and oxidative stress in experimental diabetic neuropathy. Life Sci 2006; 79:777-783.