The effects of anticonvulsants on 4-aminopyridine-induced bursting: in vitro studies on rat peripheral nerve and dorsal roots.
1. Aminopyridines have been used as beneficial symptomatic treatments in a variety of neurological conditions including multiple sclerosis but have been associated with considerable toxicity in the form of abdominal pain, paraesthesias and (rarely) convulsions. 2. Extracellular and intracellular recording was used to characterize action potentials in rat sciatic nerves and dorsal roots and the effects of 4-aminopyridine (4-AP). 3. In sciatic nerve trunks, 1 mM 4-AP produced pronounced after potentials at room temperature secondary to regenerative firing in affected axons (5-10 spikes per stimulus). At physiological temperatures, after potentials (2-3 spikes) were greatly attenuated in peripheral axons. 4. 4-AP evoked more pronounced and prolonged after discharges in isolated dorsal roots at 37 degrees C (3-5.5 mV and 80-100 ms succeeded by a smaller inhibitory/depolarizing voltage shift) which were used to assess the effects of anticonvulsants. 5. Phenytoin, carbamazepine and lamotrigine dose-dependently reduced the area of 4-AP-induced after potentials at 100 and 320 microM but the amplitude of compound action potentials (evoked at 0.5 Hz) was depressed in parallel. 6. The tonic block of sensory action potentials by all three drugs (at 320 microM) was enhanced by high frequency stimulation (5-500 Hz). 7. The lack of selectivity of these frequency-dependent Na+ channel blockers for burst firing compared to low-frequency spikes, is discussed in contrast to their effects on 4-AP-induced seizures and paroxysmal activity in CNS tissue (which is associated with large and sustained depolarizing plateau potentials). 8. In conclusion, these in vitro results confirm the marked sensitivity of sensory axons to 4-AP (the presumptive basis for paraesthesias). Burst firing was not preferentially impaired at relatively high concentrations suggesting that anticonvulsants will not overcome the toxic peripheral actions of 4-AP in neurological patients.
Lees
G
G
Department of Academic Anaesthetics, Imperial College of Medicine, London.
D015761:4-Aminopyridine / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D018408:Patch-Clamp Techniques; D010525:Peripheral Nerves / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000166:cytology / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013696:Temperature
D000927:Anticonvulsants; D015222:Sodium Channels; D015761:4-Aminopyridine