title: The anti-nociceptive agent ralfinamide inhibits tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ currents in dorsal root ganglion neurons.
abstract: Tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ channels contribute to the abnormal spontaneous firing in dorsal root ganglion neurons associated with neuropathic pain. Effects of the anti-nociceptive agent ralfinamide on tetrodotoxin-resistant and tetrodotoxin-sensitive currents in rat dorsal root ganglion neurons were therefore investigated by patch clamp experiments. Ralfinamide inhibition was voltage-dependent showing highest potency towards inactivated channels. IC50 values for tonic block of half-maximal inactivated tetrodotoxin-resistant and tetrodotoxin-sensitive currents were 10 microM and 22 microM. Carbamazepine, an anticonvulsant used in the treatment of pain, showed significantly lower potency. Ralfinamide produced a hyperpolarising shift in the steady-state inactivation curves of both currents confirming the preferential interaction with inactivated channels. Additionally, ralfinamide use and frequency dependently inhibited both currents and significantly delayed repriming from inactivation. All effects were more pronounced for tetrodotoxin-resistant than tetrodotoxin-sensitive currents. The potency and mechanisms of actions of ralfinamide provide a hypothesis for the anti-nociceptive properties found in animal models.
authors.affiliation: Research and Development, Newron Pharmaceuticals S.p.A., Via L. Ariosto 21, I-20091 Bresso, Milan, Italy.
authors.forename: Tina C
authors.initials: TC
authors.lastname: Stummann
authors.forename: Patricia
authors.initials: P
authors.lastname: Salvati
authors.forename: Ruggero G
authors.initials: RG
authors.lastname: Fariello
authors.forename: Laura
authors.initials: L
authors.lastname: Faravelli
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology; D004351:Drug Resistance; D005071:Evoked Potentials / Q000187:drug effects; D005464:Fluorobenzenes / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000700:Analgesics; D005464:Fluorobenzenes; D015222:Sodium Channels; C499681:Ralfinamide; D002220:Carbamazepine; D013779:Tetrodotoxin