title: Antisense-mediated knockdown of Na(V)1.8, but not Na(V)1.9, generates inhibitory effects on complete Freund's adjuvant-induced inflammatory pain in rat.
abstract: Tetrodotoxin-resistant (TTX-R) sodium channels Na(V)1.8 and Na(V)1.9 in sensory neurons were known as key pain modulators. Comparing with the widely reported Na(V)1.8, roles of Na(V)1.9 on inflammatory pain are poorly studied by antisense-induced specific gene knockdown. Here, we used molecular, electrophysiological and behavioral methods to examine the effects of antisense oligodeoxynucleotide (AS ODN) targeting Na(V)1.8 and Na(V)1.9 on inflammatory pain. Following complete Freund's adjuvant (CFA) inflammation treatment, Na(V)1.8 and Na(V)1.9 in rat dorsal root ganglion (DRG) up-regulated mRNA and protein expressions and increased sodium current densities. Immunohistochemical data demonstrated that Na(V)1.8 mainly localized in medium and small-sized DRG neurons, whereas Na(V)1.9 only expressed in small-sized DRG neurons. Intrathecal (i.t.) delivery of AS ODN was used to down-regulate Na(V)1.8 or Na(V)1.9 expressions confirmed by immunohistochemistry and western blot. Unexpectedly, behavioral tests showed that only Na(V)1.8 AS ODN, but not Na(V)1.9 AS ODN could reverse CFA-induced heat and mechanical hypersensitivity. Our data indicated that TTX-R sodium channels Na(V)1.8 and Na(V)1.9 in primary sensory neurons played distinct roles in CFA-induced inflammatory pain and suggested that antisense oligodeoxynucleotide-mediated blocking of key pain modulator might point toward a potential treatment strategy against certain types of inflammatory pain.
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, the Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Yao-Qing
authors.initials: YQ
authors.lastname: Yu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Su-Min
authors.initials: SM
authors.lastname: Guan
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006967:Hypersensitivity / Q000150:complications / Q000235:genetics / Q000473:pathology; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000473:pathology; D007278:Injections, Spinal; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000150:complications* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C568319:Scn10a protein, rat; C113705:Scn11a protein, rat; D015222:Sodium Channels; D005620:Freund's Adjuvant