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.
Bowe
C M
CM
Department of Pediatrics, Brown University, Providence, RI 02912.
Kocsis
J D
JD
Targ
E F
EF
Waxman
S G
SG
D015761:4-Aminopyridine; D000200:Action Potentials; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D005260:Female; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D009043:Motor Activity / Q000502:physiology*; D009186:Myelin Sheath / Q000187:drug effects*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012677:Sensation / Q000502:physiology*; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000502:physiology
D000631:Aminopyridines; D008244:Lysophosphatidylcholines; D015761:4-Aminopyridine