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

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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.

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References

  • Ahmed AZO, Moustafa HM, Saida ALY, Randa ADH, Samy AR (2006) Attenuation of morphine tolerance and dependence by aminoguanidine in mice. Eur J Pharmacol 540:60–66

    Article  Google Scholar 

  • Calcutt NA, Backonja MM (2007) Pathogenesis of pain in peripheral diabetic neuropathy. Curr Diabetes Rep 7:429–434

    Article  Google Scholar 

  • Cameron NE, Cotter MA (2008) Pro-inflammatory mechanis neuropathy: focus on the nuclear factor kappa B pathway. Curr Drug Targets 9(1):60–67

    Article  PubMed  CAS  Google Scholar 

  • 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):121–126

    Article  Google Scholar 

  • 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):153–160

    Article  PubMed  CAS  Google Scholar 

  • 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 285:63–70

    PubMed  CAS  Google Scholar 

  • D’Amour WL, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79

    Google Scholar 

  • 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 151:322–329

    PubMed  CAS  Google Scholar 

  • 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 94:2157–2163

    Article  PubMed  CAS  Google Scholar 

  • 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):1371–1377

    PubMed  CAS  Google Scholar 

  • 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):525–529

    Article  CAS  Google Scholar 

  • Green LC, Wagner DA, Glogowski J (1982) Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids. Anal Biochem 126(1):131–138

    Article  PubMed  CAS  Google Scholar 

  • 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 399:161–164

    Article  PubMed  CAS  Google Scholar 

  • 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):331–334

    Google Scholar 

  • Hargreaves KM, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88

    Article  PubMed  CAS  Google Scholar 

  • Hide I, Tanaka M, Inoue A (2000) Extracellular ATP triggers tumor necrosis factor alpha release from rat microglia. J Neurochem 75:965–972

    Article  PubMed  CAS  Google Scholar 

  • Ibironke GF, Saba OJ (2006) Effect of hyperglycemia on the efficacy of morphine analgesia in rats. Afr J Med Sci 5(4):443–445

    Google Scholar 

  • Jana HL, Daniel JC, Douglas GM, Richard CM (1999) Effect of hyperglycemia on pain threshold in alloxan-diabetic rats. Pain 40(1):105–107

    Google Scholar 

  • 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):66–71

    Article  PubMed  CAS  Google Scholar 

  • 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):7353–7365

    Article  PubMed  CAS  Google Scholar 

  • Juan PC, Han-Rong W, Patrick MD (2008) The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats. Brain Res 1229:100–110

    Article  Google Scholar 

  • 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):139–142

    Article  PubMed  CAS  Google Scholar 

  • 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):1553–1558

    Article  CAS  Google Scholar 

  • Kolb H, Kroncke KD (1993) IDDM: lessons from the low-dose streptozotocin model in mice. Diabetes Rev 1:116–126

    Google Scholar 

  • Like AA, Rossini AA (1976) Streptozotocin-induced pancreatic insulitis: a new model of diabetes mellitus. Science 193:415–417

    Article  PubMed  CAS  Google Scholar 

  • 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):593–598

    Google Scholar 

  • Maryam B, Zeinab K (2010) Short-and long-term modulation of microvascular responses in streptozotocin-induced diabetic rats by glycosylated products. J Diabetes Complicat 24:64–72

    Article  Google Scholar 

  • 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):142–149

    Article  PubMed  CAS  Google Scholar 

  • 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 23:1026–1040

    PubMed  CAS  Google Scholar 

  • 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 56:1371–1377

    Google Scholar 

  • 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–E1655

    Article  PubMed  CAS  Google Scholar 

  • 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):113–117

    CAS  Google Scholar 

  • 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 29:327–334

    Article  PubMed  CAS  Google Scholar 

  • Raz I, Hasdai D, Seltzer Z, Melmed RN (1988) Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes 37:1253–1259

    Article  PubMed  CAS  Google Scholar 

  • 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):699–703

    Article  PubMed  CAS  Google Scholar 

  • Satoh J, Yagihashi S, Toyota T (2003) The possible role of tumor necrosis factor-α in diabetic polyneuropathy. Exp Diabesity Res 4:65–71

    Article  PubMed  Google Scholar 

  • Schafer M (2009) Novel concepts for analgesia in severe pain-current strategies and future innovations. Eur J Pain Suppl 3(1):6–10

    Article  Google Scholar 

  • 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 553:99–103

    Article  Google Scholar 

  • 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):266–269

    Article  PubMed  CAS  Google Scholar 

  • Smith LF, Lohmann AB, Dewey WL (1999) Involvement of phospholipid signal transduction pathways in morphine tolerance in mice. Br J Pharmacol 128:220–226

    Article  PubMed  CAS  Google Scholar 

  • 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):213–221

    Google Scholar 

  • Taliyan R, Singh M, Sharma PL (2010a) Beneficial effect of cyclosporine in experimental diabetes induced neuropathic pain in rats. Intern J Pharmacol 6(4):355–361

    Google Scholar 

  • Taliyan R, Singh M, Sharma PL (2010b) Possible mechanism of hyperglycemia induced decrease in antinociceptive effect of analgesics in rats. IJPSR 1(5):99–107

    CAS  Google Scholar 

  • Timothy SB, John WC (1997) The role of nuclear factor k B in cytokine gene regulation. Am J Respir Cell Mol Biol 17:3–9

    Google Scholar 

  • Tsiklauri N, Tsagareli MG (2006) Non-opioid-induced tolerance in rats. Neuropyhysiology 38:314–317

    Article  CAS  Google Scholar 

  • 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):471–484

    Article  PubMed  CAS  Google Scholar 

  • 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):469–471

    PubMed  CAS  Google Scholar 

  • Ziegler D (2008) Treatment of diabetic neuropathy and neuropathic pain: how far have we come? Diabetes Care 31(2):S255–261

    Google Scholar 

  • Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    Article  PubMed  CAS  Google Scholar 

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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.

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Correspondence to Rajeev Taliyan.

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Taliyan, R., Sharma, P.L. Possible mechanism of protective effect of thalidomide in STZ-induced-neuropathic pain behavior in rats. Inflammopharmacol 20, 89–97 (2012). https://doi.org/10.1007/s10787-011-0106-4

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  • DOI: https://doi.org/10.1007/s10787-011-0106-4

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