batrachotoxinin-a-20-alpha-benzoate and capsazepine

This investigation was conducted to provide further insight into the effects of vanilloid (subtype 1) receptor (VR1) drugs at voltage-gated sodium channels and examine the potential of this interaction to influence release of neurotransmitters from synaptosomes prepared from mammalian brain. The VR1 modulatory drugs capsaicin, olvanil and capsazepine inhibited the binding of batrachotoxinin-A 20-alpha-benzoate ([(3)H]BTX-B) to receptor site 2 of voltage-gated sodium channels. All drugs reduced the affinity of radioligand for sodium channels, and capsazepine also decreased the number of [(3)H]BTX-B binding sites. In kinetic experiments, no reduction in radioligand association rate was found, but capsaicin, olvanil and capsazepine all enhanced the dissociation rate of [(3)H]BTX-B. All drugs inhibited veratridine-evoked release of L-glutamic acid, gamma-amino butyric acid and L-aspartic acid from synaptosomes; however, their inhibitory effects on transmitter release were much weaker when 35 mM potassium chloride was used to depolarize synaptosomes. The study compounds, in common with other central nervous system depressants, interact with a region on the voltage-gated sodium channel that permits negative allosteric coupling with receptor site 2 and this mechanism likely accounts for blockade of sodium channel-activated transmitter release.

Topics: Animals; Aspartic Acid; Batrachotoxins; Brain; Capsaicin; gamma-Aminobutyric Acid; Glutamic Acid; Male; Mice; Mice, Inbred Strains; Potassium Chloride; Sodium Channels; Synaptosomes; Tritium; TRPV Cation Channels; Veratridine