Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury.
Spinal cord injury (SCI) can result in hyperexcitability of dorsal horn neurons and central neuropathic pain. We hypothesized that these phenomena are consequences, in part, of dysregulated expression of voltage-gated sodium channels. Because the rapidly repriming TTX-sensitive sodium channel Nav1.3 has been implicated in peripheral neuropathic pain, we investigated its role in central neuropathic pain after SCI. In this study, adult male Sprague Dawley rats underwent T9 spinal contusion injury. Four weeks after injury when extracellular recordings demonstrated hyperexcitability of L3-L5 dorsal horn multireceptive nociceptive neurons, and when pain-related behaviors were evident, quantitative RT-PCR, in situ hybridization, and immunocytochemistry revealed an upregulation of Nav1.3 in dorsal horn nociceptive neurons. Intrathecal administration of antisense oligodeoxynucleotides (ODNs) targeting Nav1.3 resulted in decreased expression of Nav1.3 mRNA and protein, reduced hyperexcitability of multireceptive dorsal horn neurons, and attenuated mechanical allodynia and thermal hyperalgesia after SCI. Expression of Nav1.3 protein and hyperexcitability in dorsal horn neurons as well as pain-related behaviors returned after cessation of antisense delivery. Responses to normally noxious stimuli and motor function were unchanged in SCI animals administered Nav1.3 antisense, and administration of mismatch ODNs had no effect. These results demonstrate for the first time that Nav1.3 is upregulated in second-order dorsal horn sensory neurons after nervous system injury, showing that SCI can trigger changes in sodium channel expression, and suggest a functional link between Nav1.3 expression and neuronal hyperexcitability associated with central neuropathic pain.
Hains
Bryan C
BC
Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Klein
Joshua P
JP
Saab
Carl Y
CY
Craner
Matthew J
MJ
Black
Joel A
JA
Waxman
Stephen G
SG
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D004195:Disease Models, Animal; D004594:Electrophysiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D062552:NAV1.3 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000150:complications / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009619:Nociceptors / Q000473:pathology / Q000503:physiopathology; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D062552:NAV1.3 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C478638:Scn3a protein, rat; D015222:Sodium Channels