AUTHOR=Jonas Robin , Prato Vincenzo , Lechner Stefan G. , Groen Gerbrand , Obreja Otilia , Werland Fiona , Rukwied Roman , Klusch Andreas , Petersen Marlen , Carr Richard W. , Schmelz Martin 

TITLE=TTX-Resistant Sodium Channels Functionally Separate Silent From Polymodal C-nociceptors

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=14

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2020.00013

DOI=10.3389/fncel.2020.00013

ISSN=1662-5102

ABSTRACT=<p>Pronounced activity-dependent slowing of conduction has been used to characterize mechano-insensitive, “silent” nociceptors and might be due to high expression of Na<sub>V</sub>1.8 and could, therefore, be characterized by their tetrodotoxin-resistance (TTX-r). Nociceptor-class specific differences in action potential characteristics were studied by: (i) <italic>in vitro</italic> calcium imaging in single porcine nerve growth factor (NGF)-responsive neurites; (ii) <italic>in vivo</italic> extracellular recordings in functionally identified porcine silent nociceptors; and (iii) <italic>in vitro</italic> patch-clamp recordings from murine silent nociceptors, genetically defined by nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) expression. Porcine TTX-r neurites (<italic>n</italic> = 26) <italic>in vitro</italic> had more than twice as high calcium transients per action potential as compared to TTX-s neurites (<italic>n</italic> = 18). In pig skin, silent nociceptors (<italic>n</italic> = 14) characterized by pronounced activity-dependent slowing of conduction were found to be TTX-r, whereas polymodal nociceptors were TTX-s (<italic>n</italic> = 12) and had only moderate slowing. Mechano-insensitive cold nociceptors were also TTX-r but showed less activity-dependent slowing than polymodal nociceptors. Action potentials in murine silent nociceptors differed from putative polymodal nociceptors by longer duration and higher peak amplitudes. Longer duration AP in silent murine nociceptors linked to increased sodium load would be compatible with a pronounced activity-dependent slowing in pig silent nociceptors and longer AP durations could be in line with increased calcium transients per action potential observed <italic>in vitro</italic> in TTX-resistant NGF responsive porcine neurites. Even though there is no direct link between slowing and TTX-resistant channels, the results indicate that axons of silent nociceptors not only differ in their receptive but also in their axonal properties.</p>