Differential slow inactivation and use-dependent inhibition of Na _v1.8 channels contribute to distinct firing properties in IB ₄⁺ and IB₄^- DRG neurons

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) Na_v1.8 channels are expressed in both IB₄⁺ and IB ₄^- 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 Na_v1.8 current in IB ₄⁺ neurons is significantly stronger than that in IB ₄^- neurons, although voltage dependency of activation and steady-state inactivation are not different. The time constant for entry of Na_v1.8 into slow inactivation in IB₄⁺ neurons is significantly faster and more Na_v1.8 enter the slow inactivation state than in IB₄^- neurons. In addition, recovery from slow inactivation of Na_v1.8 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 Na_v1.8 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.