A nociceptor excitability test for identifying alterations of the Nav1.7 channels in humans

Sodium channel variants are associated with small fiber neuropathy. While in vitro recordings allow detailed assessment of sodium channel function, their contribution to peripheral small nerve fiber excitability remains unstudied. The perception threshold tracking (PTT) method allows indirect assessment of small fiber function by transcutaneous electrical stimulation and psychophysics. Here, we developed a Sodium channel Excitability Nociceptor Test that allows for the identification of alterations in selected subtypes of sodium channels in small fibers of awake humans. We hypothesize that due to the unique dynamics of sodium channels, it is possible to derive a nerve excitability test to uniquely identify alterations in the Na v 1.7 channel. Using a multicompartmental nerve fiber model, a set of 5 electrical pulse shapes was developed. These pulse shapes consist of rectangular and ramp test pulses preceded by either a hyperpolarizing or depolarizing prepulse. To validate the predictive power of our in silico simulations, we used an automated whole-cell patch clamp on Na v 1.7 expressed in HEK293T cells and a PTT experiment in healthy participants. The computational model predicted that an alteration of Na v 1.7 can be classified with an accuracy of 92% (n = 30) when the standard deviation of the perception threshold is 11%, which was measured by the PTT experiment. The peak Na v 1.7 current elicited in vitro corresponded well with the prediction of the in silico model. The study thus provides an excitability test to predict the involvement of Na v 1.7, and potentially also Na v 1.8 and Na v 1.9, in the generation of neuropathic pain in small fiber neuropathy.