Inhibition of Nav1.7 and Nav1.4 sodium channels by trifluoperazine involves the local anesthetic receptor

Patrick Sheets, Peter Gerner, Chi Fei Wang, Sho Ya Wang, Kuo Wang Ging, Theodore Cummins

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 Nav1.7 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 μM TFP induce major decreases in Nav1.7 and Nav1.4 current amplitudes and that 2 μM TFP causes hyperpolarizing shifts in the steady-state inactivation of Na v1.7 and Nav1.4. 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 Nav1.7 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.

Original languageEnglish
Pages (from-to)1848-1859
Number of pages12
JournalJournal of Neurophysiology
Volume96
Issue number4
DOIs
StatePublished - Oct 2006

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Trifluoperazine
Sodium Channels
Local Anesthetics
Calmodulin
Inhibition (Psychology)
Voltage-Gated Sodium Channels
Nociception
Conduction Anesthesia
Peripheral Nervous System
Sciatic Nerve
Pain Management
Analgesia
Dialysis

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

Cite this

Inhibition of Nav1.7 and Nav1.4 sodium channels by trifluoperazine involves the local anesthetic receptor. / Sheets, Patrick; Gerner, Peter; Wang, Chi Fei; Wang, Sho Ya; Ging, Kuo Wang; Cummins, Theodore.

In: Journal of Neurophysiology, Vol. 96, No. 4, 10.2006, p. 1848-1859.

Research output: Contribution to journalArticle

Sheets, Patrick ; Gerner, Peter ; Wang, Chi Fei ; Wang, Sho Ya ; Ging, Kuo Wang ; Cummins, Theodore. / Inhibition of Nav1.7 and Nav1.4 sodium channels by trifluoperazine involves the local anesthetic receptor. In: Journal of Neurophysiology. 2006 ; Vol. 96, No. 4. pp. 1848-1859.
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