Excitability of regenerated fibers remains impaired due to changes in both passive cable properties and alterations in the voltage-dependent membrane function. These abnormalities were studied by mathematical modeling in human regenerated nerves and experimental studies in mice. In three adult male patients with surgically repaired complete injuries of peripheral nerves of the arm 22 months-26 years prior to investigation, deviation of excitability measures was explained by a hyperpolarizing shift in the resting membrane potential and an increase in the passive 'Barrett and Barrett' conductance (GBB) bridging the nodal and internodal compartments. These changes were associated with an increase in the 'fast' K(+) conductance and the inward rectifier conductance (GH). Similar changes were found in regenerated mouse tibial motor axons at 1 month after a sciatic crush lesion. During the first 5 months of regeneration, GH showed partial recovery, which paralleled that in GBB. The internodal length remained one-third of normal. Excitability abnormalities could be reversed by the energy-dependent Na(+)/K(+) pump blocker ouabain resulting in membrane depolarization. Stressing the Na(+) pumping system during a strenuous activity protocol triggered partial Wallerian degeneration in regenerated nerves but not in control nerves from age-matched mice. The current data suggest that the nodal voltage-gated ion channel machinery is restored in regenerated axons, although the electrical separation from the internodal compartment remains compromised. Due to the persistent increase in number of nodes, the increased activity-dependent Na(+) influx could lead to hyperactivity of the Na(+)/K(+) pump resulting in membrane hyperpolarization and neurotoxic energy insufficiency during strenuous activity.