Received for publication May 26, 2005.
Revised July 19, 2005.
Accepted for publication August 25, 2005.

Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage gated sodium and calcium channels

Abstract

The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50-400 µM), eperisone, lanperisone, inaperisone and silperisone (25-200 µM) dose-dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100-800 µM) produced qualitatively similar depression of spinal functions in the hemicord preparation, while 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 analogues in the [3H]-BTX binding in cortical, 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, while 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.

Key words: calcium channel, central muscle relaxant, sodium channel, spinal cord, spinal reflex, tolperisone