title: Sodium channel Na(v)1.7 is essential for lowering heat pain threshold after burn injury.
abstract: Marked hypersensitivity to heat and mechanical (pressure) stimuli develop after a burn injury, but the neural mechanisms underlying these effects are poorly understood. In this study, we establish a new mouse model of focal second-degree burn injury to investigate the molecular and cellular basis for burn injury-induced pain. This model features robust injury-induced behavioral effects and tissue-specific altered cytokine profile, but absence of glial activation in spinal dorsal horn. Three voltage-gated sodium channels, Na(v)1.7, Na(v)1.8, and Na(v)1.9, are preferentially expressed in peripheral somatosensory neurons of the dorsal root ganglia (DRGs) and have been implicated in injury-induced neuronal hyperexcitability. Using knock-out mice, we provide evidence that Na(v)1.7 selectively contributes to burn-induced hypersensitivity to heat, but not mechanical, stimuli. After burn model injury, wild-type mice display increased sensitivity to heat stimuli, and a normally non-noxious warm stimulus induces activity-dependent Fos expression in spinal dorsal horn neurons. Strikingly, both effects are absent in Na(v)1.7 conditional knock-out (cKO) mice. Furthermore, burn injury increases density and shifts activation of tetrodotoxin-sensitive currents in a hyperpolarized direction, both pro-excitatory properties, in DRG neurons from wild-type but not Na(v)1.7 cKO mice. We propose that, in sensory neurons damaged by burn injury to the hindpaw, Na(v)1.7 currents contribute to the hyperexcitability of sensory neurons, their communication with postsynaptic spinal pain pathways, and behavioral thresholds to heat stimuli. Our results offer insights into the molecular and cellular mechanisms of modality-specific pain signaling, and suggest Na(v)1.7-blocking drugs may be effective in burn patients.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Shields
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Cheng
authors.forename: Nurcan
authors.initials: N
authors.lastname: Uçeyler
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002056:Burns / Q000150:complications*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000209:etiology; D004558:Electric Stimulation; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000166:cytology; D006023:Glycoproteins / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects*; D006930:Hyperalgesia / Q000209:etiology* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009437:Neuralgia / Q000209:etiology / Q000473:pathology; D009457:Neuroglia / Q000473:pathology; D017288:Pain Threshold / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D022661:RNA, Untranslated; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000172:deficiency / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection
chemical_list: D051700:Activating Transcription Factor 3; D016207:Cytokines; D006023:Glycoproteins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D011506:Proteins; D012333:RNA, Messenger; D022661:RNA, Untranslated; C568318:Scn10a protein, mouse; C491885:Scn11a protein, mouse; C503479:Scn9a protein, mouse; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C473590:isolectin B4-binding glycoprotein, mouse; D013779:Tetrodotoxin; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium