Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1. 9-null mice

T Hoffmann, K Kistner, RW Carr, MA Nassar, PW Reeh… - Pain, 2017 - journals.lww.com
T Hoffmann, K Kistner, RW Carr, MA Nassar, PW Reeh, C Weidner
Pain, 2017journals.lww.com
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 …
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.
Lippincott Williams & Wilkins