C-fiber Specific Electrical Stimulation Paradigms that Differentially Activate Skin Nociceptor Subpopulations and Detect Activity-Dependent

In this presentation slow depolarizing electrical stimuli will be presented that selectively active polymodal and mechano-insensitive nociceptors in human skin as validated by human microneurography and axon reflex erythema. While electrical pain thresholds to such stimuli mainly reflect the level of small fiber neuropathy, tonic stimulation reveals differences between painful and painless neuropathy. While stimulation in normal skin of healthy volunteers and non-painful skin areas leads to adaptation of pain ratings there is increasing pain upon such tonic stimulation in the painful area. Mechanistic underpinnings of this activity-dependent changes of excitability will be presented including inactivation of sodium channels, after-hyperpolarization and depolarizing chloride currents. Direct links between geometry of sensory endings in the epidermis to excitability will be presented, in-particular branching patterns and axonal swelling. Implications and limitations of evoked sensory tests to probe nociceptor excitability under normal conditions and in neuropathic pain will be discussed.