title: Activation of tetrodotoxin-resistant sodium channel NaV1.9 in rat primary sensory neurons contributes to melittin-induced pain behavior.
abstract: Tetrodotoxin-resistant (TTX-R) sodium channels NaV1.8 and NaV1.9 in dorsal root ganglion (DRG) neurons play important roles in pathological pain. We recently reported that melittin, the major toxin of whole bee venom, induced action potential firings in DRG neurons even in the presence of a high concentration (500 nM) of TTX, indicating the contribution of TTX-R sodium channels. This hypothesis is fully investigated in the present study. After subcutaneous injection of melittin, NaV1.8 and NaV1.9 significantly upregulate mRNA and protein expressions, and related sodium currents also increase. Double immunohistochemical results show that NaV1.8-positive neurons are mainly medium- and small-sized, whereas NaV1.9-positive ones are only small-sized. Antisense oligodeoxynucleotides (AS ODNs) targeting NaV1.8 and NaV1.9 are used to evaluate functional significance of the increased expressions of TTX-R sodium channels. Behavioral tests demonstrate that AS ODN targeting NaV1.9, but not NaV1.8, reverses melittin-induced heat hypersensitivity. Neither NaV1.8 AS ODN nor NaV1.9 AS ODN affects melittin-induced mechanical hypersensitivity. These results provide previously unknown evidence that upregulation of NaV1.9, but not NaV1.8, in small-sized DRG neurons contributes to melittin-induced heat hypersensitivity. Furthermore, melittin-induced biological effect indicates a potential strategy to study properties of TTX-R sodium channels.
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, #1 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China.
authors.forename: Yao-Qing
authors.initials: YQ
authors.lastname: Yu
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Zhao
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D004351:Drug Resistance; D005727:Ganglia, Spinal / Q000166:cytology; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D008555:Melitten / Q000633:toxicity*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000502:physiology; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D059225:Nociception / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014110:Touch
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C568319:Scn10a protein, rat; C113705:Scn11a protein, rat; D008555:Melitten; D013779:Tetrodotoxin; D012964:Sodium