Using dynamic clamp to quantify pathological changes in the excitability of primary somatosensory neurons.

Primary somatosensory neurons become hyperexcitable in many chronic pain conditions. Hyperexcitability can include a switch from transient to repetitive spiking during sustained somatic depolarization. This switch results from diverse pathological processes that impact ion channel expression or function. Because multiple pathological processes co-occur, isolating how much each contributes to switching the spiking pattern is difficult. Our approach to this challenge involves adding a virtual sodium conductance via dynamic clamp. The magnitude of that conductance was titrated to determine the minimum required to enable rheobasic stimulation to evoke repetitive spiking. The minimum required conductance, termed g¯ Na ∗, was re-measured before and during manipulations designed to model various pathological processes in vitro. The reduction in g¯ Na ∗ caused by each pathomimetic manipulation reflects how much the modelled process contributes to switching the spiking pattern. We found that elevating extracellular potassium or applying inflammatory mediators reduced g¯ Na ∗ whereas direct hyperpolarization had no effect. Inflammatory mediators reduced g¯ Na ∗ more in medium-large (>30 μm diameter) neurons than in small (⩽30 μm diameter) neurons, but had equivalent effects in cutaneous and muscle afferents. The repetitive spiking induced by dynamic clamp was also found to differ between small and medium-large neurons, thus revealing latent differences in adaptation. Our study demonstrates a novel way to determine to what extent individual pathological factors facilitate repetitive spiking. Our results suggest that most factors facilitate but do not cause repetitive spiking on their own, and, therefore, that a switch to repetitive spiking results from the cumulative effect of many co-occurring factors.