Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8.
Neuropathic pain is a debilitating chronic syndrome that often arises from injuries to peripheral nerves. Such pain has been hypothesized to be the result of an aberrant expression and function of sodium channels at the site of injury. Here, we show that intrathecal administration of specific antisense oligodeoxynucleotides (ODN) to the peripheral tetrodotoxin (TTX)-resistant sodium channel, NaV1.8, resulted in a time-dependent uptake of the ODN by dorsal root ganglion (DRG) neurons, a selective "knock-down" of the expression of NaV1.8, and a reduction in the slow-inactivating, TTX-resistant sodium current in the DRG cells. The ODN treatment also reversed neuropathic pain induced by spinal nerve injury, without affecting non-noxious sensation or response to acute pain. These data provide direct evidence linking NaV1.8 to neuropathic pain. As NaV1.8 expression is restricted to sensory neurons, this channel offers a highly specific and effective molecular target for the treatment of neuropathic pain.
Lai
Josephine
J
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA. lai@u.arizona.edu
Gold
Michael S
MS
Kim
Chang Sook
CS
Bian
Di
D
Ossipov
Michael H
MH
Hunter
John C
JC
Porreca
Frank
F
D000779:Anesthetics, Local; D000818:Animals; D005727:Ganglia, Spinal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000032:analysis / Q000494:pharmacology; D010146:Pain / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000032:analysis / Q000096:biosynthesis* / Q000502:physiology; D013779:Tetrodotoxin
D000779:Anesthetics, Local; D020319:Oligodeoxyribonucleotides, Antisense; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin