Physiological effects of 4‐aminopyridine on demyelinated mammalian motor and sensory fibers

The selective response of demyelinated sensory fibers to 4-aminopyridine (4-AP) has been proposed as a mechanism underlying the reported paresthesias that complicate the use of this potassium-channel blocking agent in clinical trials for the treatment of multiple sclerosis and neuromuscular disorders. To identify differences in the electrophysiological response of specific fiber types to the application of 4-AP, rat ventral and dorsal spinal roots, demyelinated by intrathecal injections of lysophosphatidylcholine, were examined in vitro before and during potassium-channel blockade. The compound action potentials of demyelinated ventral roots showed a prominent postspike negativity associated with a broadening of single action potentials following application of 4-AP. Under similar conditions, whole root responses of demyelinated dorsal root axons also developed a late negativity, but individual fibers were observed to fire repetitively in response to a single stimulus. The data support the hypothesis that the prominent sensory dysfunctions reported in clinical trials of 4-AP are due to the selective response characteristics of sensory fibers.