Skip to main content
Log in

Mechanisms and pharmacology of diabetic neuropathy – experimental and clinical studies

  • Review
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Neuropathic pain is the most common chronic complication of diabetes mellitus. The mechanisms involved in the development of diabetic neuropathy include changes in the blood vessels that supply the peripheral nerves; metabolic disorders, such as the enhanced activation of the polyol pathway; myo-inositol depletion; and increased non-enzymatic glycation. Currently, much attention is focused on the changes in the interactions between the nervous system and the immune system that occur in parallel with glial cell activation; these interactions may also be responsible for the development of neuropathic pain accompanying diabetes. Animal models of diabetic peripheral neuropathy have been utilized to better understand the phenomenon of neuropathic pain in individuals with diabetes and to define therapeutic goals. The studies on the effects of antidepressants on diabetic neuropathic pain in streptozotocin (STZ)-induced type 1 diabetes have been conducted. In experimental models of diabetic neuropathy, the most effective antidepressants are tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. Clinical studies of diabetic neuropathy indicate that the first line treatment should be tricyclic antidepressants, which are followed by anticonvulsants and then opioids. In this review, we will discuss the mechanisms of the development of diabetic neuropathy and the most common drugs used in experimental and clinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Anjaneyulu M, Chopra K: Fluoxetine attenuates thermal hyperalgesia through 5-HT1/2 receptors in streptozotocin-induced diabetic mice. Eur J Pharmacol, 2004, 497, 285–292.

    Article  CAS  PubMed  Google Scholar 

  2. Beyreuther B, Callizot N, Stöhr T: Antinociceptive efficacy of lacosamide in a rat model for painful diabetic neuropathy. Eur J Pharmacol, 2006, 539, 64–70.

    Article  CAS  PubMed  Google Scholar 

  3. Bishnoi M, Bosgraaf CA, Abooj M, Zhong L, Premkumar LS: Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators. Mol Pain, 2011, 7, 52.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Boyle J, Eriksson ME, Gribble L, Gouni R, Johnsen S, Coppini DV, Kerr D: Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life. Diabetes Care, 2012, 35, 2451–2458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brownlee M: Glycation products and the pathogenesis of diabetic complications; Diabetes Care, 1992, 15, 1835–1840.

    Article  CAS  PubMed  Google Scholar 

  6. Cegielska-Perun K, Bujalska-Zadrożny M, Makulska-Nowak HE: Modification of morphine analgesia by venlafaxine in diabetic neuropathic pain model. Pharmacol Rep, 2012, 64, 1267–1275.

    Article  CAS  PubMed  Google Scholar 

  7. Christoph T, De Vry J, Tzschentke TM: Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Neurosci Lett, 2010, 470, 91–94.

    Article  CAS  PubMed  Google Scholar 

  8. Clements RS Jr: Diabetic neuropathy-new concepts of its etiology. Diabetes, 1979, 28, 604–611.

    Article  CAS  PubMed  Google Scholar 

  9. Courteix C, Bardin M, Chantelauze C, Lavarenne J, Eschalier A: Study of the sensitivity of the diabetes-induced pain model in rats to a range of analgesics. Pain, 1994, 57, 153–160.

    Article  CAS  PubMed  Google Scholar 

  10. Czyżyk A: Pathophysiology and diabetes clinic (Polish). PZWL, Warszawa 1987, 146–147.

  11. Daulhac L, Mallet C, Courteix C, Etienne M, Duroux E, Privat AM, Eschalier A, Fialip J: Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol, 2006, 70, 1246–1254.

    Article  CAS  PubMed  Google Scholar 

  12. Devi P, Madhu K, Ganapathy B, Sarma G, John L, Kulkarni C: Evaluation of efficacy and safety of gabapentin, duloxetine, and pregabalin in patients with painful diabetic peripheral neuropathy. Indian J Pharmacol, 2012, 44, 51–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Dick IE, Brochu RM, Purohit Y, Kaczorowski GJ, Martin WJ, Priest BT: Sodium channel blockade may contribute to the analgesic efficacy of antidepressants. J Pain, 2007, 8, 315–324.

    Article  CAS  PubMed  Google Scholar 

  14. Drel VR, Lupachyk S, Shevalye H, Vareniuk I, Xu W, Zhang J, Delamere NA et al.: New therapeutic and bio-marker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis fac -tor-α. Endocrinology, 2010, 151, 2547–2555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dyck PJ, Karnes JL, O’Brien P, Okazaki H, Lais A, Engelstad J: The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia. Ann Neurol, 1986, 19, 440–449.

    Article  CAS  PubMed  Google Scholar 

  16. Fisher SK, Heacock AM, Agranoff BW: Inositol lipids and signal transduction in the nervous system: an update. JNeurochem, 1992, 58, 18–38.

    Article  CAS  PubMed  Google Scholar 

  17. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL: Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med, 2005, 352, 1324–1334.

    Article  CAS  PubMed  Google Scholar 

  18. Gómez-Pérez FJ, Choza R, Ríos JM, Reza A, Huerta E, Aguilar CA, Rull JA: Nortriptyline-fluphenazine vs. carbamazepine in the symptomatic treatment of diabetic neuropathy. Arch Med Res, 1996, 27, 525–529.

    PubMed  Google Scholar 

  19. Goodnick PJ, Breakstone K, Kumar A, Freund B, De-Vane CL: Nefazodone in diabetic neuropathy: response and biology. Psychosom Med, 2000, 62, 599–600.

    Article  CAS  PubMed  Google Scholar 

  20. Hanna M, O’Brien C, Wilson MC: Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain, 2008, 12, 804–813.

    Article  CAS  PubMed  Google Scholar 

  21. Hall GC, Morant SV, Carroll D, Gabriel ZL, McQuay HJ: An observational descriptive study of the epidemiology and treatment of neuropathic pain in a UK general population. BMC Fam Pract, 2013, 14–28.

  22. Ikeda T, Ishida Y, Naono R, Takeda R, Abe H, Nakamura T, Nishimori T: Effects of intrathecal administration of newer antidepressants on mechanical allodynia in rat models of neuropathic pain. Neurosci Res, 2009, 63, 42–46.

    Article  CAS  PubMed  Google Scholar 

  23. Kimura J: Electrodiagnosis in diseases of nerve and muscle – principles and practice. Davis, Philadelphia, 1987, 464.

  24. Kolosov A, Goodchild CS, Cooke I: CNSB004 (Lecono-tide) causes antihyperalgesia without side effects when given intravenously: a comparison with ziconotide in a rat model of diabetic neuropathic pain. Pain Med, 2010, 11, 262–273.

    Article  PubMed  Google Scholar 

  25. Kozma CM, Benson C, Slaton TL, Kim MS, Vorsanger GJ: Opioids before and after initiation of pregabalin in patients with diabetic peripheral neuropathy. Curr Med Res Opin, 2012, 28, 1485–1496.

    Article  CAS  PubMed  Google Scholar 

  26. Kuhad A, Bishnoi M, Chopra K: Anti-nociceptive effect of duloxetine in mouse model of diabetic neuropathic pain. Indian J Exp Biol, 2009, 47, 193–197.

    CAS  PubMed  Google Scholar 

  27. Lang F: Mechanisms and significance of cell volume regulation. J Am Coll Nutr, 2007, 26, 613–623.

    Article  Google Scholar 

  28. Lindner MD, Bourin C, Chen P, McElroy JF, Leet JE, Hogan JB, Stock DA, Machet F: Adverse effects of gabapentin and lack of anti-allodynic efficacy of amitriptyline in the streptozotocin model of painful diabetic neuropathy. Exp Clin Psychopharmacol, 2006, 14, 42–51.

    Article  CAS  PubMed  Google Scholar 

  29. Malik RA: The pathology of human diabetic neuropathy. Diabetes, 1997, 45, 50–53.

    Article  Google Scholar 

  30. Martinez JA, Kasamatsu M, Rosales-Hernandez A, Hanson LR, Frey WH, Toth CC: Comparison of central versus peripheral delivery of pregabalin in neuropathic pain states. Mol Pain, 2012, 8, article 3.

    Article  CAS  Google Scholar 

  31. Matsunami T, Sato Y, Hasegawa Y, Ariga S, Kashimura H, Sato T, Yukawa M: Enhancement of reactive oxygen species and induction of apoptosis in streptozotocin-induced diabetic rats under hyperbaric oxygen exposure. Int J Clin Exp Pathol, 2011, 4, 255–266.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med, 1992, 326, 1250–1256.

    Article  CAS  PubMed  Google Scholar 

  33. Mert T, Gunes Y: Antinociceptive activities of lidocaine and the nav1.8 blocker a803467 in diabetic rats. J Am Assoc Lab Anim Sci, 2012, 51, 579–585.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mika J, Osikowicz M, Rojewska E, Korostyński M, Wawrzczak-Bargieła A, Przewłocki R, Przewłocka B: Differential activation of spinal microglial and astroglial cells in a mouse model of peripheral neuropathic pain. Eur J Pharmacol, 2009, 623, 65–72.

    Article  CAS  PubMed  Google Scholar 

  35. Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, Allende-Vigo MZ, Duconge J: Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. Curr Clin Pharmacol, 2011, 6, 260–273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mixcoatl-Zecuatl T, Jolivalt CG: A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy. Br J Pharmacol, 2011, 164, 159–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT: Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain, 2007, 132, 289–300.

    Article  CAS  PubMed  Google Scholar 

  38. Oates PJ: Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol, 2002, 50, 325–392.

    Article  CAS  PubMed  Google Scholar 

  39. Ogawa K, Sasaki H, Kishi Y, Yamasaki H, Okamoto K, Yamamoto N, Hanabusa T et al.: A suspected case of proximal diabetic neuropathy predominantly presenting with scapulohumeral muscle weakness and deep aching pain. Diabetes Res Clin Pract, 2001, 54, 57–64.

    Article  CAS  PubMed  Google Scholar 

  40. Otto M, Bach FW, Jensen TS, Brřsen K, Sindrup SH: Escitalopram in painful polyneuropathy: a randomized, placebo-controlled, cross-over trial. Pain, 2008, 139, 275–283.

    Article  CAS  PubMed  Google Scholar 

  41. Pabreja K, Dua K, Sharma S, Padi SS, Kulkarni SK: Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanisms. Eur J Pharmacol, 2011, 661, 15–21.

    Article  CAS  PubMed  Google Scholar 

  42. Pavy-Le Traon A, Fontaine S, Tap G, Guidolin B, Senard JM, Hanaire H: Cardiovascular autonomic neuropathy and other complications in type 1 diabetes. Clin Auton Res, 2010, 20, 153–160.

    Article  PubMed  Google Scholar 

  43. Rowbotham MC, Goli V, Kunz NR, Lei D: Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain, 2004, 110, 697–706.

    Article  CAS  PubMed  Google Scholar 

  44. Said G: Diabetic neuropathy – a review. Nat Clin Pract Neurol, 2007, 3, 331–340.

    Article  PubMed  Google Scholar 

  45. Schwartz S, Etropolski M, Shapiro DY, Okamoto A, Lange R, Haeussler J, Rauschkolb C: Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin, 2011, 27, 151–162.

    Article  CAS  PubMed  Google Scholar 

  46. Simpson DA: Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis, 2001, 3, 53–62.

    Article  CAS  PubMed  Google Scholar 

  47. Sindrup SH, Gram LF, Skjold T, Frøland A, Beck-Nielsen H: Concentration-response relationship in imipramine treatment of diabetic neuropathy symptoms. Clin Pharmacol Ther, 1990, 47, 509–515.

    Article  CAS  PubMed  Google Scholar 

  48. Sindrup SH, Otto M, Finnerup NB, Jensen TS: Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol, 2005, 96, 399–409.

    Article  CAS  PubMed  Google Scholar 

  49. Smith H: Analgesic actions of insulin. J Neuropathic Pain Symptom Palliat, 2006, 1, 23–28.

    Article  Google Scholar 

  50. Sounvoravong S, Nakashima MN, Wada M, Nakashima K: Modification of antiallodynic and antinociceptive effects of morphine by peripheral and central action of fluoxetine in a neuropathic mice model. Acta Biol Hung, 2007, 58, 369–379.

    Article  CAS  PubMed  Google Scholar 

  51. Sundkvist G, Dahlin LB, Nilsson H, Eriksson KF, Lindgärde F, Rosén I, Lattimer SA et al.: Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance. DiabetMed, 2000, 17, 259–268.

    Article  CAS  PubMed  Google Scholar 

  52. Tatoń J.: Practical diabetology (Polish). PZWL, Warszawa 1993, 13–16, 32–34, 171, 277–305.

    Google Scholar 

  53. Tembhurne SV, Sakarkar DM: Effect of fluoxetine on an experimental model of diabetes-induced neuropathic pain perception in the rat. Indian J Pharm Sci, 2011, 73, 621–625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Thornalley PJ: Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options. Int Rev Neurobiol, 2002, 50, 37–57.

    Article  CAS  PubMed  Google Scholar 

  55. Tsuda M, Ueno H, Kataoka A, Tozaki-Saitoh H, Inoue K: Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling. Glia, 2008, 56, 378–386.

    Article  PubMed  Google Scholar 

  56. Vinik AI, Holland MT, Le Beau JM, Liuzzi FJ, Stansberry KB, Colen LB: Diabetic neuropathies. Diabetes Care, 1992, 15, 1926–1975.

    Article  CAS  PubMed  Google Scholar 

  57. Vlassara H, Brownlee M, Cerami A: Excessive nonenzymatic glycosylation of peripheral and central nervous system myelin components in diabetic rats. Diabetes, 1983, 32, 670–674.

    Article  CAS  PubMed  Google Scholar 

  58. Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF: Norman Cousins Lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun, 2007, 21, 131–146.

    Article  CAS  PubMed  Google Scholar 

  59. Wattiez AS, Libert F, Privat AM, Loiodice S, Fialip J, Eschalier A, Courteix C: Evidence for a differential opioidergic involvement in the analgesic effect of antide-pressants: prediction for efficacy in animal models of neuropathic pain? Br J Pharmacol, 2011, 163, 792–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wattiez AS, Barrière D, Dupuis A, Courteix C: Rodent models of painful diabetic neuropathy: What can we learn from them? J Diabetes Metab, 2012, https://doi.org/10.4172/2155-6156.S5–008

  61. Williams J, Haller VL, Stevens DL, Welch SP: Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception. Eur J Pharmacol, 2008, 584, 78–86.

    Article  CAS  PubMed  Google Scholar 

  62. Williams SK, Howarth NL, Devenny JJ, Bitensky MW: Structural and functional consequences of increased tubulin glycosylation in diabetes mellitus. Proc Natl Acad Sci USA, 1982, 79, 6546–6550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wilson RC: The use of low-dose trazodone in the treatment of painful diabetic neuropathy. J Am Podiatr Med Assoc, 1999, 89, 468–471.

    Article  CAS  PubMed  Google Scholar 

  64. Wodarski R, Clark AK, Grist J, Marchand F, Malcangio M: Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats. Eur J Pain, 2009, 13, 807–811.

    Article  CAS  PubMed  Google Scholar 

  65. www.diabetes.niddk.nih.gov/dm/pubs/neuropathies/Neu-ropathies_508.pdf

  66. Yamamoto H, Shimoshige Y, Yamaji T, Murai N, Aoki T, Matsuoka N: Pharmacological characterization of standard analgesics on mechanical allodynia in streptozotocin-induced diabetic rats. Neuropharmacology, 2009, 57, 403–408.

    Article  CAS  PubMed  Google Scholar 

  67. Zin CS, Nissen LM, O’Callaghan JP, Duffull SB, Smith MT, Moore BJ: A randomized, controlled trial of oxyco-done versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with prega-balin. J Pain, 2010, 11, 462–471.

    Article  CAS  PubMed  Google Scholar 

  68. Zychowska M, Rojewska E, Kreiner G, Nalepa I, Przewlocka B, Mika J: Minocycline influences the anti-inflammatory interleukins and enhances the effectiveness of morphine under mice diabetic neuropathy. J Neuroim-munol, 2013, 262, 35–45.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joanna Mika.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zychowska, M., Rojewska, E., Przewlocka, B. et al. Mechanisms and pharmacology of diabetic neuropathy – experimental and clinical studies. Pharmacol. Rep 65, 1601–1610 (2013). https://doi.org/10.1016/S1734-1140(13)71521-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/S1734-1140(13)71521-4

Key words

Navigation