A population of in silico models identifies the interplay between Nav 1.8 conductance and potassium currents as key in regulating human dorsal root ganglion neuron excitability

Background: The Nav 1.8 sodium channel has a key role in generating repetitive action potentials nociceptive human dorsal root ganglion neurons. is differentiated from other voltage-gated channels by its unusually slow inactivation kinetics and depolarised voltage-dependence of activation. These features are particularly pronounced the allow to remain active during repolarisation. Gain-of-function mutations have been linked neuropathic pain selective blockers developed as potential new analgesics. However, it not well understood how modulating conductance alters neuronal excitability this depends on balance ion expressed neurons. Methods: To investigate this, we novel computational model neuron used construct population models that mimicked inter-neuronal heterogeneity ionic conductances morphology Results: By simulating changes models, found moderately increasing led increased firing rate, expected, but beyond an inflection point caused rate decrease. We delayed rectifier M-type potassium were also critical for determining excitability. In particular, altering shifted position therefore relationship between rate. Conclusions: Our results suggest effects can depend significantly conductances, conductances.