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Ionic mechanisms in regulation of C-fiber following frequency
The sense of pain has evolved as the most direct alarm against harmful factors. However, chronic pain cases are prevalent and difficult to relieve. Symptoms are often associated with hyperexcitability and high frequency action potential (AP) conduction of physiologically slow nociceptive C-fibers. Both of these properties are largely determined by the function of ion channels, potential analgesic drug targets. Therefore, in this thesis I investigated the main contributing ion channels to the high-frequency-firing properties of a previously established C-nociceptor computational model. In this model, I incorporated a NaV 1.6 model with resurgent current, a channel well-known for facilitating fast-spiking of other neurons. Following different experimental stimulation paradigms, our model predicted both following frequencies and AP conduction capabilities under repetitive activation, as well as inherent discharge rates under prolonged constant depolarization.
Parameter-variation analysis of the model clearly illustrated that NaV 1.6 resurgent current and fast delayed rectifiers (Kdr) synergistically shaped shallow afterhyperpolarizations (AHP) and brief APs, allowing rapid post-spike excitability during repetitive activation. Furthermore, the deep AHP generated by KA was advantageous in the context of prolonged stimulation, delaying depolarization block. KA thus appears vital for the generation of prolonged high-frequency discharges. Moreover, model predictions suggested that cooperation between increased NaV 1.7 and KA densities could explain fast-spiking C-nociceptors with minimal NaV 1.6 expression. Finally, the results provided valuable insights for the utility and limitations of both experimental protocols. In agreement with multiple patterns of peripheral fibers and other neurons in the literature, I conclude that the findings of this thesis may contribute to a better understanding of how multiple ion channel subtypes underlie conduction differences between C-fiber groups and I hope it will inspire further experimental research.