Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage-gated sodium and calcium channels.
The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50-400 microM), eperisone, lanperisone, inaperisone, and silperisone (25-200 microM) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100-800 microM) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with tolperisone and its analogs in the [3H]batrachotoxinin A 20-alpha-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of tolperisone-type centrally acting muscle relaxant drugs. Furthermore, tolperisone, eperisone, and especially silperisone had a marked effect on voltage-gated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that tolperisone-type muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.
Kocsis
Pál
P
Pharmacology and Drug Safety Research, Gedeon Richter Ltd., H-1475, Budapest, 10, P.O. Box 27, Hungary.
Farkas
Sándor
S
Fodor
László
L
Bielik
Norbert
N
Thán
Márta
M
Kolok
Sándor
S
Gere
Anikó
A
Csejtei
Mónika
M
Tarnawa
István
I
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects; D008297:Male; D009046:Motor Neurons / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects*; D013116:Spinal Cord / Q000502:physiology*; D013569:Synapses / Q000187:drug effects; D013997:Time Factors; D014049:Tolperisone / Q000031:analogs & derivatives* / Q000494:pharmacology*
D015220:Calcium Channels; D009125:Muscle Relaxants, Central; D015222:Sodium Channels; D014049:Tolperisone