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J. Biol. Chem., Vol. 279, Issue 28, 29341-29350, July 9, 2004

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Early Painful Diabetic Neuropathy Is Associated with Differential Changes in Tetrodotoxin-sensitive and -resistant Sodium Channels in Dorsal Root Ganglion Neurons in the Rat^*

Shuangsong Hong, Thomas J. Morrow, Pamela E. Paulson, Lori L. Isom¶, and John W. Wiley||

From the Departments of Internal Medicine and ^¶Pharmacology, University of Michigan, Ann Arbor, Michigan 48109 and the Department of Neurology, Veterans Affairs Medical Center, Ann Arbor, Michigan 48109

Diabetic neuropathy is a common form of peripheral neuropathy, yet the mechanisms responsible for pain in this disease are poorly understood. Alterations in the expression and function of voltage-gated tetrodotoxin-resistant (TTX-R) sodium channels have been implicated in animal models of neuropathic pain, including models of diabetic neuropathy. We investigated the expression and function of TTX-sensitive (TTX-S) and TTX-R sodium channels in dorsal root ganglion (DRG) neurons and the responses to thermal hyperalgesia and mechanical allodynia in streptozotocin-treated rats between 4–8 weeks after onset of diabetes. Diabetic rats demonstrated a significant reduction in the threshold for escape from innocuous mechanical pressure (allodynia) and a reduction in the latency to withdrawal from a noxious thermal stimulus (hyperalgesia). Both TTX-S and TTX-R sodium currents increased significantly in small DRG neurons isolated from diabetic rats. The voltage-dependent activation and steady-state inactivation curves for these currents were shifted negatively. TTX-S currents induced by fast or slow voltage ramps increased markedly in neurons from diabetic rats. Immunoblots and immunofluorescence staining demonstrated significant increases in the expression of Na_v1.3 (TTX-S) and Na_v 1.7 (TTX-S) and decreases in the expression of Na_v 1.6 (TTX-S) and Na_v1.8 (TTX-R) in diabetic rats. The level of serine/threonine phosphorylation of Na_v 1.6 and In Na_v1.8 increased in response to diabetes. addition, increased tyrosine phosphorylation of Na_v1.6 and Na_v1.7 was observed in DRGs from diabetic rats. These results suggest that both TTX-S and TTX-R sodium channels play important roles and that differential phosphorylation of sodium channels involving both serine/threonine and tyrosine sites contributes to painful diabetic neuropathy.

Received for publication, April 14, 2004

^* This work was supported by Grants RO1 DK52387 and DK 45820 from the National Institutes of Health (to J. W. W.) and Grant RG2882 from the National Multiple Sclerosis Society (to L. L. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Internal Medicine, University of Michigan Hospital, A7007 UH, Box 0108, 1500 East Medical Center Dr., Ann Arbor, MI 48109-0108. Tel.: 734-936-8080; Fax: 734-936-4024; E-mail: jwiley{at}med.umich.edu.

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