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Inflammopharmacology

, Volume 20, Issue 2, pp 89–97 | Cite as

Possible mechanism of protective effect of thalidomide in STZ-induced-neuropathic pain behavior in rats

  • Rajeev Taliyan
  • Pyare Lal Sharma
Research Article

Abstract

Introduction

Diabetes-induced neuropathic pain is recognized as one of the most difficult type of pain to treat and conventional analgesics are well known to be partially effective or associated with potential toxicity. Recently, it has been demonstrated that thalidomide, besides its teratogenic potential, reduced chronic pain in an SNL experimental pain model.

Objective

The present study was designed to investigate the effect of thalidomide on streptozotocin (STZ)-induced neuropathic pain in rats.

Materials and methods

Streptozotocin (20 mg/kg, i.p, daily × 4 days) was administered to induce diabetes in the rats. Nociceptive latency was measured using tail-flick and paw-withdrawal test. Thermal hyperalgesia and mechanical allodynia were measured using planter test and dynamic aesthesiometer (Ugo-Basile, Italy), respectively. Urinary and serum nitrite concentration was estimated using Greiss reagent method. Spleen homogenate supernatant was prepared from spleen of 28th day diabetic rats and administered to normal rats (400 ul, i.v) daily for 28 days.

Results

Pain threshold progressively decreased in STZ-treated rats, as compared with control rats. 3 weeks after induction of diabetes, the rat exhibited thermal hyperalgesia and mechanical allodynia. The analgesic effect of morphine (8 mg/kg, s.c.) was significantly decreased in both diabetic and in SHS-treated non-diabetic rats. Administration of thalidomide (25 and 50 mg/kg, i.p), a TNF-α inhibitor, significantly prevented hyperglycemia-induced thermal hyperalgesia and mechanical allodynia and also attenuated the increase in serum and urinary nitrite concentration, as compared with untreated diabetic rats. Also, thalidomide (25 and 50 mg/kg, i.p) 1 h before or concurrently with morphine significantly restored the analgesic effect of morphine in diabetic rats.

Conclusion

It may be concluded that thalidomide has a beneficial effect in neuropathic pain by decreasing cytokines (TNF-α) and nitric oxide level and may provide a novel promising therapeutic approach for managing painful diabetic neuropathy.

Keywords

Spleen homogenate supernatant (SHS) Streptozotocin (STZ) Hyperalgesia Neuropathic pain Nitric oxide Hyperglycemia 

Notes

Acknowledgments

This work is dedicated to the fond memory of our esteemed colleague, Prof Manjeet Singh who expired while this work was in progress. The author’s are also grateful to Mr. Parveen Garg, Chairmen-ISF College–Moga, India, for providing research fund and facilities.

References

  1. Ahmed AZO, Moustafa HM, Saida ALY, Randa ADH, Samy AR (2006) Attenuation of morphine tolerance and dependence by aminoguanidine in mice. Eur J Pharmacol 540:60–66CrossRefGoogle Scholar
  2. Calcutt NA, Backonja MM (2007) Pathogenesis of pain in peripheral diabetic neuropathy. Curr Diabetes Rep 7:429–434CrossRefGoogle Scholar
  3. Cameron NE, Cotter MA (2008) Pro-inflammatory mechanis neuropathy: focus on the nuclear factor kappa B pathway. Curr Drug Targets 9(1):60–67PubMedCrossRefGoogle Scholar
  4. Chen SR, Samoriski G, Pan HL (2009) Antinociceptive effects of chronic administration of uncompetitive NMDA receptor antagonists in a rat model of diabetic neuropathic pain. Neuropharmacology 257(2):121–126CrossRefGoogle Scholar
  5. Courteix C, Bardin M, Chantelauze C, Lavarenne J, Eschalier A (1994) Study of the sensitivity of the diabetes-induced pain model in rats to a range of analgesics. Pain 57(2):153–160PubMedCrossRefGoogle Scholar
  6. Courteix C, Bourget P, Caussade F, Bardin M, Coudore F, Fialip F, Eschalier A (1998) Is the reduced efficacy of morphine in diabetic rats caused by alterations of opiate receptors or of morphine pharmacokinetics? J Pharmacol Exp Ther 285:63–70PubMedGoogle Scholar
  7. D’Amour WL, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79Google Scholar
  8. Deng W, Theil B, Tannenbaum CS, Hamilton TA, Stuehr DJ (1993) Synergistic co-operation between T cell lymphokines for induction of nitric oxide synthase in murine peritoneal macrophages. J Immunol 151:322–329PubMedGoogle Scholar
  9. Doupis J, Lyons Thomas E, Szuhuei Wu, Charalambos G, Thanh D, Aristidis V (2009) Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J Clin Endocrinol Metab 94:2157–2163PubMedCrossRefGoogle Scholar
  10. Empl M, Renaud S, Erne B, Fuhr P, Straube A, Schaeren-Wiemers N, Steck AJ (2001) TNF-alpha expression in painful and nonpainful neuropathies. Neurology 56(10):1371–1377PubMedGoogle Scholar
  11. Gonzalez-Clemente JM, Mauricio D, Richart C, Broch M, Caixàs A, Megia A, Giménez-Palop O, Simón I, Martínez-Riquelme A, Giménez-Pérez G, Vendrell J (2005) Diabetic neuropathy is associated with activation of the TNF-α system in subjects with type 1 diabetes mellitus. Clin Endocrinol 63(5):525–529CrossRefGoogle Scholar
  12. Green LC, Wagner DA, Glogowski J (1982) Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids. Anal Biochem 126(1):131–138PubMedCrossRefGoogle Scholar
  13. Grover VS, Sharma A, Singh M (2000) Role of nitric oxide in diabetes-induced attenuation of antinociceptive effect of morphine in mice. Eur J Pharmacol 399:161–164PubMedCrossRefGoogle Scholar
  14. Guo LZ, Ye HW, Hui LT, Zhi BL (2001) Effect of aminoguanidine on nitric oxide production induced by inflammatory cytokines and endotoxin in cultured rat hepatocytes. World J Gastroenterol 7(3):331–334Google Scholar
  15. Hargreaves KM, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88PubMedCrossRefGoogle Scholar
  16. Hide I, Tanaka M, Inoue A (2000) Extracellular ATP triggers tumor necrosis factor alpha release from rat microglia. J Neurochem 75:965–972PubMedCrossRefGoogle Scholar
  17. Ibironke GF, Saba OJ (2006) Effect of hyperglycemia on the efficacy of morphine analgesia in rats. Afr J Med Sci 5(4):443–445Google Scholar
  18. Jana HL, Daniel JC, Douglas GM, Richard CM (1999) Effect of hyperglycemia on pain threshold in alloxan-diabetic rats. Pain 40(1):105–107Google Scholar
  19. Joharchi K, Jorjani M (2007) The role of nitric oxide in diabetes-induced changes of morphine tolerance in rats. Eur J Pharmacol 570(1–3):66–71PubMedCrossRefGoogle Scholar
  20. Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, Langer S, Martin D, Green P, Fleshner M, Leinwand L, Maier SF, Watkins LR (2004) A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 24(33):7353–7365PubMedCrossRefGoogle Scholar
  21. Juan PC, Han-Rong W, Patrick MD (2008) The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats. Brain Res 1229:100–110CrossRefGoogle Scholar
  22. Kamei J, Kawashima N, Kasuya Y (1992) Role of spleen or spleen products in the deficiency in morphine-induced analgesia in diabetic mice. Brain Res 576(1):139–142PubMedCrossRefGoogle Scholar
  23. Kamei J, Iwamoto Y, Misawa M, Nagase H, Kasuya Y (1994) Evidence for differential modulation of μ-opioid receptor-mediated antinociceptive and antitussive activities by spleen-derived factor(s) from diabetic mice. Neuropharmacol 33(12):1553–1558CrossRefGoogle Scholar
  24. Kolb H, Kroncke KD (1993) IDDM: lessons from the low-dose streptozotocin model in mice. Diabetes Rev 1:116–126Google Scholar
  25. Like AA, Rossini AA (1976) Streptozotocin-induced pancreatic insulitis: a new model of diabetes mellitus. Science 193:415–417PubMedCrossRefGoogle Scholar
  26. Ling YU, Fu-Shan Xue, Li CW, Xu Ya-Chao, Guo-Hua Z, Kun-Peng L, Yi L, Hai-Tao S (2006) Nω-nitro-l-arginine methyl ester inhibits the up-regulated expression of neuronal nitric oxide synthase/NMDA receptor in the morphine analgesia tolerance rats. Acta Physiologica Sinica 58(6):593–598Google Scholar
  27. Maryam B, Zeinab K (2010) Short-and long-term modulation of microvascular responses in streptozotocin-induced diabetic rats by glycosylated products. J Diabetes Complicat 24:64–72CrossRefGoogle Scholar
  28. Mika J, Osikowicz M, Makuch W, Przewlocka B (2007) Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain. Eur J Pharmacol 560(2–3):142–149PubMedCrossRefGoogle Scholar
  29. Milligan ED, Twining C, Chacur M, Biedenkapp J, O’Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR (2003) Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 23:1026–1040PubMedGoogle Scholar
  30. Monika E, Renaud S, Erne B, Fuhr P, Straube A, Schaeren–Wiemers N, Steck AJ (2001) TNF-alpha expression in painful and nonpainful neuropathies. Neurology 56:1371–1377Google Scholar
  31. Obrosova IG, Drel VR, Oltman CL, Mashtalir N, Tibrewala J, Groves JT, Yorek MA (2007) Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats. Am J Physiol Endocrinol Metab 293:E1645–E1655PubMedCrossRefGoogle Scholar
  32. Oka M, Sakuma Y, Kato Y, Ueda Y (2002) Large dose of thalidomide are effective for inhibiting mechino-allodynia after the onset of neuropathic pain. J Osaka Dent Univ 36(2):113–117Google Scholar
  33. Raghavendra V, Rutkowski MD, DeLeo JA (2004) Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 29:327–334PubMedCrossRefGoogle Scholar
  34. Raz I, Hasdai D, Seltzer Z, Melmed RN (1988) Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes 37:1253–1259PubMedCrossRefGoogle Scholar
  35. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G (1991) Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 173(3):699–703PubMedCrossRefGoogle Scholar
  36. Satoh J, Yagihashi S, Toyota T (2003) The possible role of tumor necrosis factor-α in diabetic polyneuropathy. Exp Diabesity Res 4:65–71PubMedCrossRefGoogle Scholar
  37. Schafer M (2009) Novel concepts for analgesia in severe pain-current strategies and future innovations. Eur J Pain Suppl 3(1):6–10CrossRefGoogle Scholar
  38. Shingo Y, Yasuyuki S, Mitsutoshi Y, Yoshio K, Shuichi T, Satoshi W, Masaki A, Ken-ichi M (2006) Antinociceptive effect of methyl eugenol on formalin induced hyperalgesia in mice. Eur J Pharmacol 553:99–103CrossRefGoogle Scholar
  39. Shukla KP, Tang L, Wang ZJ (2006) Phosphorylation of neurogranin, protein kinase C, and Ca2+/calmodulin dependent protein kinase II in opioid tolerance and dependence. Neurosci Lett 404(3):266–269PubMedCrossRefGoogle Scholar
  40. Smith LF, Lohmann AB, Dewey WL (1999) Involvement of phospholipid signal transduction pathways in morphine tolerance in mice. Br J Pharmacol 128:220–226PubMedCrossRefGoogle Scholar
  41. Stanislava DS, Danijela DM, Marija BMS, Miodrag LL (2001) Pentoxifylline prevents autoimmune mediated inflammation in low dose streptozotocin induced diabetes. Devel Immunol 8(3–4):213–221Google Scholar
  42. Taliyan R, Singh M, Sharma PL (2010a) Beneficial effect of cyclosporine in experimental diabetes induced neuropathic pain in rats. Intern J Pharmacol 6(4):355–361Google Scholar
  43. Taliyan R, Singh M, Sharma PL (2010b) Possible mechanism of hyperglycemia induced decrease in antinociceptive effect of analgesics in rats. IJPSR 1(5):99–107Google Scholar
  44. Timothy SB, John WC (1997) The role of nuclear factor k B in cytokine gene regulation. Am J Respir Cell Mol Biol 17:3–9Google Scholar
  45. Tsiklauri N, Tsagareli MG (2006) Non-opioid-induced tolerance in rats. Neuropyhysiology 38:314–317CrossRefGoogle Scholar
  46. Wei XH, Zang Y, Wu CY, Xu JT, Xin WJ, Liu XG (2007) Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodynia via upregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway. Exp Neurol 205(2):471–484PubMedCrossRefGoogle Scholar
  47. Yu LN, Yang XS, Hua Z, Xie W (2009) Serum levels of pro-inflammatory cytokines in diabetic patients with peripheral neuropathic pain and the correlation among them. Zhonghua Yi Xue Za Zhi 89(7):469–471PubMedGoogle Scholar
  48. Ziegler D (2008) Treatment of diabetic neuropathy and neuropathic pain: how far have we come? Diabetes Care 31(2):S255–261Google Scholar
  49. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  1. 1.I.S.F College of Pharmacy-MogaMogaIndia
  2. 2.KIET School of PharmacyGhaziabadIndia

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