DEPLETION OF EXTRACELLULAR POTASSIUM LEADS TO AN ACCUMULATION OF INTRA-AXONAL SODIUM AND ONGOING ACTIVITY IN MOUSE C-FIBRES VIA NaV1.9
Authors: Julius Pakalniskis, Tal Hoffmann, Christian Weidner, Katrin Kistner, Roberto De Col, Karl Messlinger, Mohammad A. Nassar, Peter W. Reeh, Richard W. Carr

Background and Aim:
Bouts of spontaneous pain in chronic pain patients are typically attributed to aberrant activity in unmyelinated C-fibres.  The processes leading to the generation of ongoing activity in C-fibres following injury have not been established. Here we ask whether uninjured “naïve” unmyelinated C-fibres can develop ongoing activity. 
Methods:
C-fibre compound action potential (C-CAP) and single fibre recordings from in cutaneous afferents in combination with calcium imaging from acutely isolated DRG neuronal somata were used to assess the effects on somatosensory neurons of extracellular potassium depletion.
Results:
Depletion of extracellular potassium from the nerve terminals of single cutaneous C-fibres led to the development of ongoing burst activity that began within approximately 20 minutes and was sustained for several hours. CAP recordings from sural nerve axons revealed a progressive decrease in the amplitude of the C-fibre elevation during depletion of extracellular potassium. Repeated increases in calcium transients were also observed in DRG neuronal somata during low potassium. In mice constitutively lacking the sodium channel isoform NaV1.9, the development of ongoing burst activity in single C-fibres , the increase in intra-axonal sodium in axons and calcium waves in DRG neuronal somata and were all ameliorated. The HCN blocker ZD7288 (10-30µM) curtailed burst length during potassium depletion.
Conclusion:
Sustained ongoing action potential activity can be generated in uninjured C-fibres using depletion of extracellular potassium. C-CAP amplitude progressively decreased suggesting an increase in intracellular sodium and this is primary dependent upon NaV1.9.

DEPLETION OF EXTRACELLULAR POTASSIUM LEADS TO AN ACCUMULATION OF INTRA-AXONAL SODIUM AND ONGOING ACTIVITY IN MOUSE C-FIBRES VIA NAV1.9