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Spinal Cord

Structure and Function in Diabetes

  • Chapter
Diabetic Neuropathy

Part of the book series: Clinical Diabetes ((CLD))

Abstract

The spinal cord is a relatively understudied target of diabetes. In this chapter an overview of the anatomy of the spinal cord and its associated structures is presented before reviewing the published literature describing evidence for structural damage to the spinal cord reported in both diabetic patients and animal models of diabetes. Spinal cord pathology is accompanied by functional disorders and diabetic rodents are being increasingly used to investigate the neurochemical and molecular mechanisms that contribute to impaired structure and function. The aetiological mechanisms that lead from hyperglyacemia to disruption of spinal cord structure and function are only beginning to be explored. The growing appreciation of the role that the spinal cord plays in modulating sensory input to and motor output from the central nervous system should prompt wider interest in diabetes-induced spinal cord injury that will complement studies of diabetic encephalopathy and peripheral neuropathy.

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References

  1. Eaton SE, Harris ND, Rajbhandarim SM, et al. Spinal-cord involvement in diabetic peripheral neuropathy. Lancet 2001;358:35–36.

    Article  PubMed  CAS  Google Scholar 

  2. Diamond MC, Scheibel AB, Elson LM. The Human Brain Coloring Book. Harper Collins, New York, NY, 1985.

    Google Scholar 

  3. Harper AA, Lawson SN. Conduction velocity is related to morphological cell type in rat dorsal root ganglion neurons. J Physiol 1985;359:31–46.

    PubMed  CAS  Google Scholar 

  4. Lee KH, Chung K, Chung JM, Coggeshall RE. Correlation of cell body size, axon size, and signal conduction velocity for individually labeled dorsal root ganglion cells in the cat. J Comp Neurol 1986;243:335–346.

    Article  PubMed  CAS  Google Scholar 

  5. Williamson RT. Changes in the posterior columns of the spinal cord in diabetes mellitus. Brit Med J 1894;1:398–399.

    Google Scholar 

  6. Williamson RT. Changes in the spinal cord in diabetes mellitus. Brit Med J 1904;1:122–123.

    Google Scholar 

  7. Woltman HW, Wilder RM. Pathologic changes in the spinal cord and peripheral nerves. Arch Intern Med 1929;44:576–603.

    Google Scholar 

  8. Dolman CL. The morbid anatomy of diabetic neuropathy. Neurology 1963;13:135–142.

    PubMed  CAS  Google Scholar 

  9. Olsson Y, Säve-Söderbergh J, Sourander P, Angervall L. A patho-anatomical study of the central and peripheral nervous system in diabetes of early onset and long duration. Path Europ 1968;3:62–79.

    CAS  Google Scholar 

  10. Olsson Y, Sourander P. Changes in the sympathetic nervous system in diabetes mellitus. A preliminary report. J Neurovisc Relat 1968;31:86–95.

    Article  PubMed  CAS  Google Scholar 

  11. Reske-Nielsen E, Lundbaek K. Pathological changes in the central and peripheral nervous system of young long-term diabetics. Diabetologia 1968;4:34–43.

    Article  PubMed  CAS  Google Scholar 

  12. Slager U. Diabetic myelopathy. Arch Pathol Lab Med 1978;102:467–469.

    PubMed  CAS  Google Scholar 

  13. Greenbaum D, Richardson PC, Salmon MV, Urich H. Pathological observations on six cases of diabetic neuropathy. Brain 1964;87:201–214.

    Article  PubMed  CAS  Google Scholar 

  14. Reidel H. Systematische morphologische untersuchungen am rückenmark von diabetikern. Zbl Allg Path 1965;107:506–513.

    Google Scholar 

  15. Kott E, Bechar M, Bornstein B, Sandbank U. Demyelination of the posterior and anterior columns of the spinal cord in association with metabolic disturbances. Israel J Med Sci 1971;7:577–580.

    PubMed  CAS  Google Scholar 

  16. Slager UT, Webb AT. Pathologic findings in the spinal cord. Arch Pathol 1973;96:388–394.

    PubMed  CAS  Google Scholar 

  17. Ohnishi A, Harada M, Tateishi J, Ogata J, Kawanami S. Segmental demyelination and remyelination in lumbar spinal roots of patients dying with diabetes mellitus. Ann Neurol 1983;13:541–548.

    Article  PubMed  CAS  Google Scholar 

  18. Schmidt RE, Dorsey D, Parvin CA, Beaudet LN, Plurad SB, Roth KA. Dystrophic axonal swellings develop as a function of age and diabetes in human dorsal root ganglia. J Neuropathol Exp Neurol 1997;56:1028–1043.

    PubMed  CAS  Google Scholar 

  19. Schmidt RE. Neuropathology and pathogenesis of diabetic autonomic neuropathy. Int Rev Neurobiol 2002;50:257–292.

    Article  PubMed  CAS  Google Scholar 

  20. De Jong RN. CNS manifestations of diabetes mellitus. Postgrad Med 1977;61:101–107.

    Google Scholar 

  21. Sidenius P, Jakobsen J. reduced perikaryal volume of lower motor and primary sensory neurons in early experimental diabetes. Diabetes 1980;29:182–186.

    Article  PubMed  CAS  Google Scholar 

  22. Jakobsen J. Axonal dwindling in early experimental diabetes. I. A study of cross sectioned nerves. Diabetologia 1976; 12:539–546.

    Article  PubMed  CAS  Google Scholar 

  23. Jakobsen J. Earlyt and preventable changes of peripheral nerve structure and function in insulin-deficient diabetic rats. J Neurol Neurosurg Psychiatr 1979;42:509–518.

    PubMed  CAS  Google Scholar 

  24. Felton DL. Spinal cord alterations in streptozotocin-induced diabetes. Anat Rec 1979;193:741–742.

    Google Scholar 

  25. Yagihashi S, Zhang WX, Sima AA. Neuroaxonal dystrophy in distal symmetric sensory polyneuropathy of the diabetic BB-rat. J Diabet Complications 1989;3:202–210.

    Article  PubMed  CAS  Google Scholar 

  26. Russell JW, Sullivan KA, Windebank AJ, Herrman DN, Feldman EL. Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis 1999;6:347–363.

    Article  PubMed  CAS  Google Scholar 

  27. Zochodne DW, Verge VM, Cheng C, Sun H, Johnston J. Does diabetes target ganglion neurones? Progressive sensory neurone involvement in long-term experimental diabetes. Brain 2001;124:2319–2334.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. Noorafshan A, Ebrahimpoor MR, Sadeghi Y. Stereological study of the cells if dorsal root ganglia in male diabetic rats. APMIS 2001;109:762–766.

    Article  PubMed  CAS  Google Scholar 

  30. Kennedy JM, Zochodne DW. Experimental diabetic neuropathy with spontaneous recovery: Is there irreparable damage? Diabetes 2005;54:830–837.

    Article  PubMed  CAS  Google Scholar 

  31. Uehara K, Yamagishi S, Otsuki S, Chin S, Yagihashi S. Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic mice. Diabetes 2004;53:3239–3247.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  33. Cheng C, Zochodne DW. Sensory neurons with activated caspase-3 survive long-term experimental diabetes. Diabetes 2003;52:2363–2371.

    Article  PubMed  CAS  Google Scholar 

  34. Sasaki H, Schmelzer JD, Zollman PJ, Low PA. Neuropathology and blood flow of nerve, spinal roots and dorsal root ganglia in longstanding diabetic rats. Acta Neuropathol 1997;93:118–128.

    Article  PubMed  CAS  Google Scholar 

  35. Lui J, Atamna H, Kuratsuune H, Ames BN. Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann NY Acad Sci 2002;959:133–166.

    Google Scholar 

  36. Tamura E, Parry GJ. Severe radicular pathology in rats with longstanding diabetes. J Neurol Sci 1994;127:29–35.

    Article  PubMed  CAS  Google Scholar 

  37. Mizisin AP, Bache M, DiStefano PS, Acheson A, Lindsay RM, Calcutt NA. BDNF attenuates functional and structural disorders in nerves of galactose-fed rats. J Neuropathol Exp Neurol 1997;56:1290–1301.

    PubMed  CAS  Google Scholar 

  38. Mizisin AP, Kalichman MW, Bache M, Dines KC, DiStefano PS. NT-3 attenuates functional and structural disorders in sensory nerves of galactose-fed rats. J Neuropathol Exp Neurol 1998;57:803–813.

    Article  PubMed  CAS  Google Scholar 

  39. Mizisin AP, Steinhardt RC, O’Brien JS, Calcutt NA. TX14(A), a prosaposin-derived peptide, reverses established nerve disorders in streptozotocin-diabetic rats and prevents them in galactose-fed rats. J Neuropathol Exp Neurol 2001;60:953–960.

    PubMed  CAS  Google Scholar 

  40. Berge BN, Wolf A, Simms HS. Degenerative lesions of spinal roots and peripheral nerves in aging rats. Gerontologia 1962;6:72–80.

    Google Scholar 

  41. Downie AW, Newell DJ. Sensory nerve conduction in patients with diabetes mellitus and controls. Neurology 1961;11:876–882.

    PubMed  CAS  Google Scholar 

  42. Lawrence DG, Locke S. Motor nerve conduction velocity in diabetes. Arch Neurol 1961;5: 483–489.

    PubMed  CAS  Google Scholar 

  43. Gupta PR, Dorfman LJ. Spinal somatosensory conduction in diabetes. Neurology 1981;31: 841–845.

    PubMed  CAS  Google Scholar 

  44. Nakamura R, Noritake M, Hosoda Y, Kamakura K, Nagata N, Shibasaki H. Somatosensory conduction delay in central and peripheral nervous system of diabetic patients. Diabetes Care 1992;5:532–535.

    Article  Google Scholar 

  45. Varsik P, Kucera P, Buranova D, Balaz M. Is the spinal cord lesion rare in diabetes mellitus? Somatosensory evoked potentials and central conduction time in diabetes mellitus. Med Sci Monit 2001;5:712–715.

    Google Scholar 

  46. Cracco J, Castells S, Mark E. Spinal somatosensory evoked potentials in juvenile diabetes. Ann Neurol 1984;15:55–58.

    Article  PubMed  CAS  Google Scholar 

  47. Suzuki C, Ozaki I, Tanosaki M, Sudam T, Baba M, Matsunaga M. Peripheral and central conduction abnormalities in diabetes mellitus. Neurology 2000;54:1932–1937.

    PubMed  CAS  Google Scholar 

  48. Maetzu C, Villoslada C, Cruz Martinez A. Somatosensory evoked potentials and central motor pathways conduction after magnetic stimulation of the brain in diabetes. Electromyogr Clin Neurophysiol 1995;35:443–448.

    PubMed  CAS  Google Scholar 

  49. Carsten RE, Whalen LR, Ishii DN. Impairment of spinal cord conduction velocity in diabetic rats. Diabetes 1989;38:730–736.

    Article  PubMed  CAS  Google Scholar 

  50. Terada M, Yasuda H, Kikkawa R, Koyama N, Yokota T, Shigeta Y. Electrophysiological study of dorsal column function in streptozocin-induced diabetic rats: comparison with 2,5-hexanedione intoxication. J Neurol Sci 1993; 115:58–66.

    Article  PubMed  CAS  Google Scholar 

  51. Biessels GJ, Cristino NA, Rutten GJ, Hamers FP, Erkelens DW, Gispen WH. Neurophysiological changes in the central and peripheral nervous system of streptozotocindiabetic rats. Course of development and effects of insulin treatment. Brain 1999; 122: 757–768.

    Article  PubMed  Google Scholar 

  52. Calcutt NA, Freshwater JD, O’Brien JS. Protection of sensory function and antihyperalgesic properties of a prosaposin-derived peptide in diabetic rats. Anesthesiology 2000;93:1271–1278.

    Article  PubMed  CAS  Google Scholar 

  53. Pertovaara A, Wei H, Kalmari J, Ruotsalainen M. Pain behavior and response properties of spinal dorsal horn neurons following experimental diabetic neuropathy in the rat: modulation by nitecapone, a COMT inhibitor with antioxidant properties. Exp Neurol 2001; 167:25–34.

    Article  CAS  Google Scholar 

  54. Chen SR, Pan HL. Hypersensitivity of spinothalamic tract neurons associated with diabetic neuropathic pain in rats. J Neurophysiol 2002;87:2726–2733.

    PubMed  Google Scholar 

  55. Kimura S, Taname M, Honda M, Ono H. Enhanced wind up of the c-fiber-mediated nociceptive flexor movement following painful diabetic neuropathy in mice. J Pharmacol Sci 2005;97:195–202.

    Article  PubMed  CAS  Google Scholar 

  56. Burchiel KJ, Russell LC, Lee RP, Sima AA. Spontaneous activity of primary afferent neurons in diabetic BB/Wistar rats. A possible mechanism of chronic diabetic neuropathic pain. Diabetes 1985;34:1210–1213.

    Article  PubMed  CAS  Google Scholar 

  57. Ahlgren SC, Levine JD. Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat. J Neurophysiol 1994;72:684–692.

    PubMed  CAS  Google Scholar 

  58. Chen X, Levine JD. Hyper-responsivity in a subset of C-fiber nociceptors in a model of painful diabetic neuropathy in the rat. Neuroscience 2001;102:185–192.

    Article  PubMed  CAS  Google Scholar 

  59. Khan GM, Chen SR, Pan HL. Role of primary afferent nerves in allodynia caused by diabetic neuropathy in rats. Neuroscience 2002;114:291–299.

    Article  PubMed  CAS  Google Scholar 

  60. Ahlgren SC, White DM, Levine JD. Increased responsiveness of sensory neurons in the saphenous nerve of the streptozotocin-diabetic rat. J Neurophysiol 1992;68:2077–2085.

    PubMed  CAS  Google Scholar 

  61. Russell LC, Burchiel KJ. Abnormal activity in diabetic rat saphenous nerve. Diabetes 1993;42:814–819.

    Article  PubMed  CAS  Google Scholar 

  62. Calcutt NA, Malmberg AB. Basal and formalin-evoked spinal levels of amino acids in conscious diabetic rats. Soc Neurosci Abs 1995;21:650.

    Google Scholar 

  63. Garrett NE, Malcangio M, Dewhurst M, Tomlinson DR. alpha-Lipoic acid corrects neuropeptide deficits in diabetic rats via induction of trophic support. Neurosci Lett 1997;222:191–194.

    Article  PubMed  CAS  Google Scholar 

  64. Calcutt NA, Chen P, Hua XY. Effects of diabetes on tissue content and evoked release of calcitonin gene-related peptide-like immunoreactivity from rat sensory nerves. Neurosci Lett 1998;254:129–132.

    Article  PubMed  CAS  Google Scholar 

  65. Calcutt NA, Stiller C, Gustafsson H, Malmberg AB. Elevated substance-P-like immunoreactivity levels in spinal dialysates during the formalin test in normal and diabetic rats. Brain Res 2000;856:20–27.

    Article  PubMed  CAS  Google Scholar 

  66. Tomlinson DR, Fernyhough P, Diemel LT, Maeda K. Deficient neurotrophic support in the aetiology of diabetic neuropathy. Diabetes Med 1996; 13:679–681.

    Article  CAS  Google Scholar 

  67. Freshwater JD, Svensson CI, Malmberg AB, Calcutt NA. Elevated spinal cyclooxygenase and prostaglandin release during hyperalgesia in diabetic rats. Diabetes 2002;51: 2249–2255.

    Article  PubMed  CAS  Google Scholar 

  68. Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 1992;257:1276–1279.

    Article  PubMed  CAS  Google Scholar 

  69. Svensson CI, Yaksh TL. The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing. Annu Rev Pharmacol Toxicol 2002;42:553–583.

    Article  PubMed  CAS  Google Scholar 

  70. Miller G. The dark side of glia. Science 2005;305:778–781.

    Article  Google Scholar 

  71. Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci 2005;28:101–107.

    Article  PubMed  CAS  Google Scholar 

  72. Fambrough DM. Control of acetylcholine receptors in skeletal muscle. Physiol Rev 1979;59:165–227.

    PubMed  CAS  Google Scholar 

  73. Kamei J, Ogawa M, Kasuya Y. Development of supersensitivity to substance P in the spinal cord of the streptozotocin-induced diabetic rats. Pharmacol Biochem Behav 1990;35: 473–475.

    Article  PubMed  CAS  Google Scholar 

  74. Li N, Young MM, Bailey CJ, Smith ME. NMDA and AMPA glutamate receptor subtypes in the thoracic spinal cord in lean and obese-diabetic ob/ob mice. Brain Res 1999;849: 34–44.

    Article  PubMed  CAS  Google Scholar 

  75. Tomiyama M, Furusawa K, Kamijo M, Kimura T, Matsunaga M, Baba M. Upregulation of mRNAs coding for AMPA and NMDA receptor subunits and metabotropic glutamate receptors in the dorsal horn of the spinal cord in a rat model of diabetes mellitus. Mol Brain Res 2005;136:275–281.

    Article  PubMed  CAS  Google Scholar 

  76. Chen SR, Pan HL. Antinociceptive effect of morphine, but not mu opioid receptor number, is attenuated in the spinal cord of diabetic rats. Anesthesiology 2003;99:1409–1414.

    Article  PubMed  CAS  Google Scholar 

  77. Chen SR, Sweigart KL, Lakoski JM, Pan HL. Functional mu opioid receptors are reduced in the spinal cord dorsal horn of diabetic rats. Anesthesiology 2002;97:1602–1608.

    Article  PubMed  CAS  Google Scholar 

  78. Bitar MS, Bajic KT, Farook T, Thomas MI, Pilcher CW. Spinal cord noradrenergic dynamics in diabetic and hypercortisolaemic states. Brain Res 1999;830:1–9.

    Article  PubMed  CAS  Google Scholar 

  79. Chen SR, Pan HL. Up-regulation of spinal muscarinic receptors and increased antinociceptive effect of intrathecal muscarine in diabetic rats. J Pharmacol Exp Ther 2003; 307:676–681.

    Article  PubMed  CAS  Google Scholar 

  80. Ongali B, Campos MM, Petcu M, et al. Expression of kinin B1 receptors in the spinal cord of streptozotocin-diabetic rat. Neuroreport 2004;15:2463–2466.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  82. Malcangio M, Tomlinson DR. A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain 1998;76:151–157.

    Article  PubMed  CAS  Google Scholar 

  83. Courteix C, Bourget P, Caussade F, et al. Is the reduced efficacy of morphine in diabetic rats caused by alterations of opiate receptors or of morphine pharmacokinetics? J Pharmacol Exp Ther 1998;285:63–70.

    PubMed  CAS  Google Scholar 

  84. Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976;17:1031–1036.

    Article  PubMed  CAS  Google Scholar 

  85. Lee YH, Ryu TG, Park SJ, et al. Alpha1-adrenoceptors involvement in painful diabetic neuropathy: a role in allodynia. Neuroreport 2000;11:1417–1420.

    Article  PubMed  CAS  Google Scholar 

  86. Bitar MS, Pilcher CW. Attenuation of IGF-1 antinociceptive action and a reduction in spinal cord gene expression of its receptor in experimental diabetes. Pain 1998;75:69–74.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, University of California San Diego, La Jolla, CA

    Andrew P. Mizisin, Corinne G. Jolivalt & Nigel A. Calcutt

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  1. Andrew P. Mizisin
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  2. Corinne G. Jolivalt
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  3. Nigel A. Calcutt
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Editors and Affiliations

  1. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

    Aristidis Veves MD, DSc

  2. Manchester Royal Infirmary and University of Manchester, Manchester, UK

    Rayaz A. Malik MBChB, PhD

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© 2007 Humana Press Inc., Totowa, NJ

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Mizisin, A.P., Jolivalt, C.G., Calcutt, N.A. (2007). Spinal Cord. In: Veves, A., Malik, R.A. (eds) Diabetic Neuropathy. Clinical Diabetes. Humana Press. https://doi.org/10.1007/978-1-59745-311-0_10

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  • DOI: https://doi.org/10.1007/978-1-59745-311-0_10

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-626-9

  • Online ISBN: 978-1-59745-311-0

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