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

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2004 May 5

PMID 15123645

Citations 91

Authors

Shuangsong Hong

Thomas J Morrow

Pamela E Paulson

Lori L Isom

John W Wiley

Affiliations

Soon will be listed here.

Abstract

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(v)1.3 (TTX-S) and Na(v) 1.7 (TTX-S) and decreases in the expression of Na(v) 1.6 (TTX-S) and Na(v)1.8 (TTX-R) in diabetic rats. The level of serine/threonine phosphorylation of Na(v) 1.6 and In Na(v)1.8 increased in response to diabetes. addition, increased tyrosine phosphorylation of Na(v)1.6 and Na(v)1.7 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.

Citing Articles

Modulation of pain sensitivity by Ascl1- and Lhx6-dependent GABAergic neuronal function in streptozotocin diabetic mice.

Hwang S, Rahman M, Go E, Roh J, Park R, Lee S Mol Ther. 2025; 33(2):786-804.

PMID: 39741412 PMC: 11852955. DOI: 10.1016/j.ymthe.2024.12.039.

A Novel Antigen Design Strategy to Isolate Single-Domain Antibodies that Target Human Nav1.7 and Reduce Pain in Animal Models.

Martina M, Banderali U, Yogi A, Arbabi Ghahroudi M, Liu H, Sulea T Adv Sci (Weinh). 2024; 11(40):e2405432.

PMID: 39206821 PMC: 11516162. DOI: 10.1002/advs.202405432.

Isolation and Culture of Adult Rat Dorsal Root Ganglion Neurons for the In Vitro Analysis of Peripheral Nerve Degeneration and Regeneration.

Sango K, Takaku S, Niimi N, Yako H Methods Mol Biol. 2024; 2831:301-313.

PMID: 39134858 DOI: 10.1007/978-1-0716-3969-6_20.

Computational modeling to study the impact of changes in Nav1.8 sodium channel on neuropathic pain.

Kan P, Zhu Y, Ma J, Singh G Front Comput Neurosci. 2024; 18:1327986.

PMID: 38784679 PMC: 11111952. DOI: 10.3389/fncom.2024.1327986.

Differential expression of slow and fast-repriming tetrodotoxin-sensitive sodium currents in dorsal root ganglion neurons.

Tan Z, Wu B, Su X, Zhou Y, Ji Y Front Mol Neurosci. 2024; 16:1336664.

PMID: 38273939 PMC: 10808659. DOI: 10.3389/fnmol.2023.1336664.

References

Kral M, Xiong Z, Study R . Alteration of Na+ currents in dorsal root ganglion neurons from rats with a painful neuropathy. Pain. 1999; 81(1-2):15-24. DOI: 10.1016/s0304-3959(98)00264-4. View

Gold M, Levine J, Correa A . Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J Neurosci. 1998; 18(24):10345-55. PMC: 6793376. View

Ratcliffe C, Qu Y, McCormick K, Tibbs V, Dixon J, Scheuer T . A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase beta. Nat Neurosci. 2000; 3(5):437-44. DOI: 10.1038/74805. View

Blackburn-Munro G, Fleetwood-Walker S . The sodium channel auxiliary subunits beta1 and beta2 are differentially expressed in the spinal cord of neuropathic rats. Neuroscience. 1999; 90(1):153-64. DOI: 10.1016/s0306-4522(98)00415-1. View

Hall K, Liu J, Sima A, Wiley J . Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathy. J Neurophysiol. 2001; 86(2):760-70. DOI: 10.1152/jn.2001.86.2.760. View

Ahlgren S, Levine J . Mechanical hyperalgesia in streptozotocin-diabetic rats. Neuroscience. 1993; 52(4):1049-55. DOI: 10.1016/0306-4522(93)90551-p. View

Wang Y, Wagner M, Kumar R, Cheng J, Joyner R . Inhibition of fast sodium current in rabbit ventricular myocytes by protein tyrosine kinase inhibitors. Pflugers Arch. 2003; 446(4):485-91. DOI: 10.1007/s00424-003-1061-8. View

Craner M, Klein J, Renganathan M, Black J, Waxman S . Changes of sodium channel expression in experimental painful diabetic neuropathy. Ann Neurol. 2002; 52(6):786-92. DOI: 10.1002/ana.10364. View

Lyu Y, Park S, Chung K, Chung J . Low dose of tetrodotoxin reduces neuropathic pain behaviors in an animal model. Brain Res. 2000; 871(1):98-103. DOI: 10.1016/s0006-8993(00)02451-3. View

10.

Porreca F, Lai J, Bian D, Wegert S, Ossipov M, Eglen R . A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci U S A. 1999; 96(14):7640-4. PMC: 33594. DOI: 10.1073/pnas.96.14.7640. View

11.

Black J, Renganathan M, Waxman S . Sodium channel Na(v)1.6 is expressed along nonmyelinated axons and it contributes to conduction. Brain Res Mol Brain Res. 2002; 105(1-2):19-28. DOI: 10.1016/s0169-328x(02)00385-6. View

12.

Fitzgerald E, Okuse K, Wood J, Dolphin A, Moss S . cAMP-dependent phosphorylation of the tetrodotoxin-resistant voltage-dependent sodium channel SNS. J Physiol. 1999; 516 ( Pt 2):433-46. PMC: 2269267. DOI: 10.1111/j.1469-7793.1999.0433v.x. View

13.

Black J, Cummins T, Plumpton C, Chen Y, Hormuzdiar W, Clare J . Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J Neurophysiol. 1999; 82(5):2776-85. DOI: 10.1152/jn.1999.82.5.2776. View

14.

Catterall W . From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 2000; 26(1):13-25. DOI: 10.1016/s0896-6273(00)81133-2. View

15.

Spruce M, Potter J, Coppini D . The pathogenesis and management of painful diabetic neuropathy: a review. Diabet Med. 2003; 20(2):88-98. DOI: 10.1046/j.1464-5491.2003.00852.x. View

16.

Yu F, Catterall W . Overview of the voltage-gated sodium channel family. Genome Biol. 2003; 4(3):207. PMC: 153452. DOI: 10.1186/gb-2003-4-3-207. View

17.

Dib-Hajj S, Tyrrell L, Black J, Waxman S . NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc Natl Acad Sci U S A. 1998; 95(15):8963-8. PMC: 21185. DOI: 10.1073/pnas.95.15.8963. View

18.

Novakovic S, Tzoumaka E, McGivern J, Haraguchi M, Sangameswaran L, Gogas K . Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions. J Neurosci. 1998; 18(6):2174-87. PMC: 6792911. View

19.

Ahlgren S, Levine J . Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat. J Neurophysiol. 1994; 72(2):684-92. DOI: 10.1152/jn.1994.72.2.684. View

20.

Djouhri L, Bleazard L, Lawson S . Association of somatic action potential shape with sensory receptive properties in guinea-pig dorsal root ganglion neurones. J Physiol. 1998; 513 ( Pt 3):857-72. PMC: 2231320. DOI: 10.1111/j.1469-7793.1998.857ba.x. View