title: Inhibition of Nav1.7 and Nav1.4 sodium channels by trifluoperazine involves the local anesthetic receptor.
abstract: The calmodulin (CaM) inhibitor trifluoperazine (TFP) can produce analgesia when given intrathecally to rats; however, the mechanism is not known. We asked whether TFP could modulate the Na(v)1.7 sodium channel, which is highly expressed in the peripheral nervous system and plays an important role in nociception. We show that 500 nM and 2 muM TFP induce major decreases in Na(v)1.7 and Na(v)1.4 current amplitudes and that 2 muM TFP causes hyperpolarizing shifts in the steady-state inactivation of Na(v)1.7 and Na(v)1.4. CaM can bind to the C-termini of voltage-gated sodium channels and modulate their functional properties; therefore we investigated if TFP modulation of sodium channels was due to CaM inhibition. However, the TFP inhibition was not replicated by whole cell dialysis of a calmodulin inhibitory peptide, indicating that major effects of TFP do not involve a disruption of CaM-channel interactions. Rather, our data show that TFP inhibition is state dependent and that the majority of the TFP inhibition depends on specific amino-acid residues in the local anesthetic receptor site in sodium channels. TFP was also effective in vivo in causing motor and sensory blockade after subfascial injection to the rat sciatic nerve. The state-dependent block of Na(v)1.7 channels with nanomolar concentrations of TFP raises the possibility that TFP, or TFP analogues, might be useful for regional anesthesia and pain management and could be more potent than traditional local anesthetics.
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Sheets
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
authors.forename: Chi-Fei
authors.initials: CF
authors.lastname: Wang
authors.forename: Sho-Ya
authors.initials: SY
authors.lastname: Wang
authors.forename: Ging Kuo
authors.initials: GK
authors.lastname: Wang
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Cummins
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000502:physiology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009124:Muscle Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D009154:Mutation; D062553:NAV1.4 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011955:Receptors, Drug / Q000187:drug effects / Q000502:physiology*; D012584:Sciatic Nerve / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D000779:Anesthetics, Local; D002147:Calmodulin; D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011955:Receptors, Drug; C106251:SCN4A protein, human; C486866:SCN9A protein, human; D015222:Sodium Channels; D014268:Trifluoperazine