title: Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1.9-null mice.
abstract: The upregulation of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 has previously been associated with inflammatory hyperalgesia. Na1.9 knockout (KO) mice, however, did not seem insensitive in conventional tests of acute nociception. Using electrophysiological, neurochemical, and behavioral techniques, we now show NaV1.9-null mice exhibit impaired mechanical and thermal sensory capacities and reduced electrical excitability of nociceptors. In single-fiber recordings from isolated skin, the electrical threshold of NaV1.9 KO C fibers was elevated by 55% and the median von Frey threshold was 32 mN in contrast to 8 mN in wild types (WTs). The prevalence of C mechano-heat-sensitive (CMH) fibers was only 25.6% in NaV1.9 KO animals compared to 75.8% in the WT group, and the heat threshold of these CMH fibers was 40.4°C in the control vs 44°C in the KO group. Compound action potential recordings from isolated sciatic nerve segments of NaV1.9 KO mice revealed lower activity-induced slowing of conduction velocity upon noxious heat stimulation: 8% vs 30% in WTs. Heat-induced calcitonin gene-related peptide release from the skin was less in the KO than in the WT group. The reduced noxious heat sensitivity was finally confirmed with the Hargreaves test using 2 rates of radiant heating of the plantar hind paws. In conclusion, NaV1.9 presumably contributes to acute thermal and mechanical nociception in mice, most likely through increasing the excitability but probably also by amplifying receptor potentials irrespective of the stimulus modality.
authors: Institute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Tal
authors: T
authors: Hoffmann
authors: Institute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Katrin
authors: K
authors: Kistner
authors: Department of Anesthesiology and Operative Intensive Care, Heidelberg University, Mannheim, Germany.
authors: Richard W
authors: RW
authors: Carr
authors: Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.
authors: Mohammed A
authors: MA
authors: Nassar
authors: Institute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Peter W
authors: PW
authors: Reeh
authors: Institute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Christian
authors: C
authors: Weidner
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D005260:Female; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000172:deficiency* / Q000235:genetics; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D009431:Neural Conduction / Q000235:genetics; D009619:Nociceptors / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation / Q000009:adverse effects; D012867:Skin / Q000294:innervation
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; C491885:Scn11a protein, mouse; D015740:Calcitonin Gene-Related Peptide