Contributions of voltage-gated sodium, calcium and potassium currents to the excitability of nociceptive sensory neurons

In this thesis I have studied how the voltage-gated conductances expressed in nociceptors control various aspects of action potential generation during stimuli of varying duration and frequency. In Chapter 2 I present experiments using the action potential clamp method to measure the TTX-sensitive sodium, TTX-resistant sodium and calcium currents flowing during nociceptor action potentials, and focus on how inactivation shapes the contributions of TTX-sensitive and TTX-resistant sodium channels. The TTX-resistant sodium current contributes the majority of charge transferred during the action potential, and due to its slow and incomplete inactivation, contributes a significant fraction of the inward charge during the action potential shoulder. Chapter 3 describes the role of TTX-resistant sodium current slow inactivation in the adaptation of firing in nociceptive sensory neurons. Although TTX-resistant sodium channels recover from fast inactivation quite quickly, their rapid entry to slow inactivation prevents nociceptors from firing continuously throughout a depolarizing stimulus. Lastly, in Chapter 4 I describe the role of K_v3 and large conductance calcium-activated potassium channels in nociceptor action potential repolarization and in action potential broadening that occurs during repetitive stimulation. These studies will help in understanding the control of nociceptor excitability, and how changes in conductances might contribute to hyperalgesic states.