Differential Slow Inactivation and Use-Dependent Inhibition of Nav1.8 Channels Contribute to Distinct Firing Properties in IB4+ and IB4− DRG Neurons

Abstract

Nociceptive dorsal root ganglion (DRG) neurons can be classified into nonpeptidergic IB4+ and peptidergic IB4− subtypes, which terminate in different layers in dorsal horn and transmit pain along different ascending pathways, and display different firing properties. Voltage-gated, tetrodotoxin-resistant (TTX-R) Nav1.8 channels are expressed in both IB4+ and IB4− cells and produce most of the current underlying the depolarizing phase of action potential (AP). Slow inactivation of TTX-R channels has been shown to regulate repetitive DRG neuron firing behavior. We show in this study that use-dependent reduction of Nav1.8 current in IB4+ neurons is significantly stronger than that in IB4− neurons, although voltage dependency of activation and steady-state inactivation are not different. The time constant for entry of Nav1.8 into slow inactivation in IB4+ neurons is significantly faster and more Nav1.8 enter the slow inactivation state than in IB4− neurons. In addition, recovery from slow inactivation of Nav1.8 in IB4+ neurons is slower than that in IB4− neurons. Using current-clamp recording, we demonstrate a significantly higher current threshold for generation of APs and a longer latency to onset of firing in IB4+, compared with those of IB4− neurons. In response to a ramp stimulus, IB4+ neurons produce fewer APs and display stronger adaptation, with a faster decline of AP peak than IB4− neurons. Our data suggest that differential use-dependent reduction of Nav1.8 current in these two DRG subpopulations, which results from their different rate of entry into and recovery from the slow inactivation state, contributes to functional differences between these two neuronal populations.