Altered expression and function of sodium channels in large DRG neurons and myelinated A-fibers in early diabetic neuropathy in the rat

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Abstract

Differential alterations of sodium channels in small nociceptive C-fiber DRG neurons have been implicated in diabetic neuropathy. In this study, we investigated sodium currents and the expression of sodium channels in large A-fiber DRG neurons in diabetic rats. Compared with controls, large neurons from diabetic rats showed significant increases in both total and TTX-S sodium currents and ∼−15 mV shifts in their voltage-dependent activation kinetics. TTX-R Nav1.9 sodium current was also significantly increased, whereas no alteration of TTX-R Nav1.8 current was observed in neurons from diabetic rats. Sodium current induced by fast- or slow-voltage ramps increased markedly in the diabetic neurons as well. Immunofluorescence studies showed significant increases in the levels and number of large DRG neurons from diabetic rats expressing Nav1.2, Nav1.3, Nav1.7, and Nav1.9 whereas Nav1.8 decreased. We also observed a decrease in the number of nodes of Ranvier expressing Nav1.8 and in staining intensity of Nav1.6 and Nav1.8 at nodes. Our results suggest that alterations of sodium channels occur in large DRG neurons and A-fibers, and may play an important role in diabetic sensory neuropathy.

Section snippets

Materials and methods

Experimental animals. Male Sprague–Dawley rats were housed in the animal facility of the University of Michigan Unit for Laboratory Animal Medicine, which was maintained at 22 °C, 55% relative humidity, with an automatic 12 h light/dark cycle. The animals received a standard laboratory diet and tap water ad libitum. All experiments were approved by the University of Michigan Committee on Use and Care of Animals according to National Institutes of Health Guidelines.

Induction of diabetes. Diabetes

Large-soma DRG neurons from diabetic rats demonstrated altered amplitude and activation kinetics of sodium currents

Using established criteria [17], we recorded sodium currents in DRG neurons with large soma to evaluate potential changes in sodium current (INa) in this population of neurons in short-term diabetes. Total INa was recorded in large DRG neurons (Cm > 70 pF) using a series of depolarizing voltage commands with a prepulse to −120 mV for 500 ms from a holding potential of −80 mV. The amplitudes of total INa at the rising phase were significantly increased in neurons from diabetic rats compared with the

Discussion

Distinct subtypes of voltage-gated sodium channels appear to play pivotal roles in pain sensation under physiologic and pathophysiologic conditions [10], [19]. In the present study, we report for the first time that large A-fiber DRG neurons demonstrated alterations in the functional properties of TTX-S INa and TTX-R Nav1.9 INa, and in the levels of sodium channel immunoreactivity in the streptozotocin-induced model of diabetic neuropathy. Total INa, TTX-S INa, and ramp current were

Acknowledgments

We thank Dr. Lori L. Isom for valuable discussion and generous gift of the sodium channel antibodies. This work was supported by Grant R01DK056997 to JWW from National Institute of Health and by Pilot/Feasibility study grant from Michigan Diabetes Research and Training Center to SH.

References (36)

  • H.A. Lekan et al.

    Sprouting of A beta fibers into lamina II of the rat dorsal horn in peripheral neuropathy

    Neurosci. Lett.

    (1996)
  • S.N. Lawson

    Phenotype and function of somatic primary afferent nociceptive neurones with C-, Adelta- or Aalpha/beta-fibres

    Exp. Physiol

    (2002)
  • E. Ochodnicka et al.

    Quantitative analysis of myelinated nerve fibers of peripheral nerve in streptozotocin-induced diabetes mellitus

    Mol. Chem. Neuropathol.

    (1995)
  • A.P. Mizisin et al.

    Myelin splitting, Schwann cell injury and demyelination in feline diabetic neuropathy

    Acta. Neuropathol. (Berl.)

    (1998)
  • L.J. Hudson et al.

    Metabotropic glutamate receptor 5 upregulation in A-fibers after spinal nerve injury: 2-methyl-6-(phenylethynyl)-pyridine (MPEP) reverses the induced thermal hyperalgesia

    J. Neurosci.

    (2002)
  • W.A. Catterall

    Structure and function of voltage-gated ion channels

    Annu. Rev. Biochem.

    (1995)
  • S.G. Waxman et al.

    Sodium channels and pain

    Proc. Natl. Acad. Sci. USA

    (1999)
  • J.N. Wood et al.

    Voltage-gated sodium channels and pain pathways

    J. Neurobiol.

    (2004)
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