Mechanisms of paresthesias arising from healthy axons

Paresthesias are common manifestations of central and peripheral pathological processes and are due to ectopic impulse activity in cutaneous afferents or their central projections. Cutaneous afferents are more excitable than motor axons, due to differences in their biophysical properties. These differences probably include more persistent Na(+) conductance and inward rectification on cutaneous afferents, properties which probably confer greater protection from impulse-dependent conduction failure but create a greater tendency to ectopic activity. Ectopic discharges can be induced in normal afferents by four maneuvers: hyperventilation, ischemia, release of ischemia, and prolonged tetanization. The alkaline shift produced by hyperventilation selectively increases the persistent Na(+) conductance, while the membrane depolarization produced by ischemia affects both transient and persistent Na(+) channels. Postischemic and posttetanic paresthesias occur when hyperpolarization by the Na(+)/K(+) pump is transiently prevented by raised extracellular K(+). The electrochemical gradient for K(+) is reversed, and inward K(+) currents trigger regenerative depolarization. These mechanisms of paresthesia generation can account for paresthesias in normal subjects and may be relevant in some peripheral nerve disorders.